Novel bicyclic sulfonamide derivatives which are L-CPT1 inhibitors

ABSTRACT

The invention is concerned with novel heterobicyclic derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , V, W, X and Y are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds inhibit L-CPT1 and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.06101580.6, filed Feb. 13, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention is concerned with novel heterobicyclic derivatives of theformula (I)

and pharmaceutically acceptable salts and esters thereof.

Further, the invention is concerned with a process for the manufactureof the above compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND

High levels of free fatty acids (FFA) lead to an increase of livermitochondrial β-oxidation, which is crucial to drive efficientgluconeogenesis. The mitochondrial oxidation of long-chain FFA requiresthe intervention of two membrane-bound carnitine-dependentpalmitoyltransferases (CPTs). CPT1, the outer mitochondrial membraneenzyme, catalyzes the formation of long-chain acylcarnitines. Liver(L-CPT1) and muscle (M-CPT1) CPT1 isoforms are encoded by two differentgenes and inhibited by malonyl-CoA. The N-ter domain of L-CPT1 confersits lower sensitivity to malonyl CoA. CPT2, the inner mitochondrialmembrane enzyme, reconverts long-chain acylcarnitines into long-chainacyl CoA esters. Long-chain acyl-CoAs are then β-oxidized to acetyl-CoA,which activates the pyruvate carboxylase and gluconeogenesis. Accordingto the mechanism of action described above, pharmaceutically activesubstances which inhibit L-CPT1 reduce liver β-oxidation, consequentlyinhibit gluconeogenesis and therefore counteract hyperglycemia.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound offormula (I):

wherein:

V is N or —C(R⁷)—; W is a single bond or —C(R⁸R⁹)—; X is O, S, SO, SO₂or N(R¹⁰); Y is —C(R¹¹R¹²)—, —C(R¹¹R¹²)C(R¹³R¹⁴)—,—C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)—, —C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)C(R¹⁷R¹⁸)— or—C(R¹¹)═C(R¹²)—;

R¹, R², R³, R⁴ and R⁵ independently from each other are hydrogen,halogen, cyano, hydroxy, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy,fluoro-lower-alkoxy, lower-alkyl-C(O), lower-alkyl-C(O)—NH,lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂, NH₂—S(O)₂,N(H,lower-alkyl)-S(O)₂ or N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), COOH or lower-alkoxy-C(O),wherein lower-alkyl is optionally substituted with hydroxy, NH₂,N(H,lower-alkyl) or N(lower-alkyl)₂;R⁶ is an aryl or heteroaryl group, which aryl or heteroaryl group isoptionally substituted by 1 to 4 substituents selected from the groupconsisting of halogen, hydroxy, cyano, lower-alkyl, fluoro-lower-alkyl,lower-alkoxy, fluoro-lower-alkoxy, lower-alkyl-C(O),lower-alkyl-C(O)—NH, lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂,NH₂—S(O)₂, N(H,lower-alkyl)-S(O)₂, N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), lower-alkoxy-C(O), COOH,1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl,5-oxo-4H-[1,2,4]thiadiazol-3-yl, 5-thioxo-4H-[1,2,4]oxadiazol-3-yl,2-oxo-3H-[1,2,3,5]oxathiadiazol-4-yl, SO₃H, 3-hydroxy-isooxazol-5-yl,6-oxo-6H-pyran-3-yl, 6-oxo-6H-pyran-2-yl, 2-oxo-2H-pyran-3-yl,2-oxo-2H-pyran-4-yl and P(O)(OCH₂CH₃)OH, wherein lower-alkyl isoptionally substituted with COOH, hydroxy, NH₂, N(H,lower-alkyl) orN(lower-alkyl)₂, and wherein fluoro-lower-alkyl is optionallysubstituted with hydroxy;

R⁷ is hydrogen, halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl,fluoro-lower-alkoxy, hydroxy or hydroxy-lower-alkyl; R⁸ and R⁹independently from each other are hydrogen or lower-alkyl; R¹⁰ ishydrogen, lower-alkyl, cycloalkyl, lower-alkyl-C(O), lower-alkyl-S(O)₂,lower-alkoxy-C(O), (lower-alkyl)NH—C(O), or (lower-alkyl)₂N—C(O); R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ independently from each other arehydrogen, halogen, hydroxy, lower alkyl, lower-alkoxy,fluoro-lower-alkyl, fluoro-lower-alkoxy, hydroxy-lower-alkyl, aryl,COOH, C(O)O-lower-alkyl or cyano;

and pharmaceutically acceptable salts and esters thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of compounds of formula (I), comprising the step of:

reacting a compound of formula (XIV)

with a compound of formula (XV)

orreacting a compound of formula (XVI)

with a compound R⁶—NH₂,wherein R¹, R², R³, R⁴, R⁵, R⁶, V, W, X and Y are as defined above.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I and a pharmaceuticallyacceptable carrier and/or adjuvant.

In a still another embodiment of the present invention, provided is amethod for the therapeutic and/or prophylactic treatment of diseaseswhich are modulated by L-CPT1 inhibitors, comprising the step ofadministering a therapeutically effective amount of a compound accordingto formula I to a human being or animal in need thereof.

DETAILED DESCRIPTION

The present invention relates to novel compounds which inhibit livercarnitine palmitoyl transferase 1 (L-CPT1) activity. The compounds ofthe present invention can be used as pharmaceutically active agentswhich are useful in the prevention and/or treatment of diseases whichare modulated by L-CPT1 inhibitors, particularly diseases which arerelated to hyperglycemia and/or glucose tolerance disorders. Suchdiseases include e.g. diabetes and associated pathologies, non insulindependent diabetes mellitus (also referred to as diabetes type II),obesity, hypertension, insulin resistance syndrome, metabolic syndrome,hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure.

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. Lower-alkyl groups asdescribed below also are preferred alkyl groups. Alkyl groups canoptionally be substituted with hydroxy, NH₂, N(H,lower-alkyl) orN(lower-alkyl)₂ or COOH. Unless specifically mentioned, unsubstitutedalkyl groups are preferred.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like. Lower-alkyl groupscan optionally be substituted with hydroxy, NH₂, N(H,lower-alkyl),N(lower-alkyl)₂. or COOH. Unless specifically mentioned, unsubstitutedlower-alkyl groups are preferred. The term “carboxy-lower-alkyl” refersto a lower-alkyl group which is substituted with COOH. The term“hydroxy-lower-alkyl” refers to a lower-alkyl group which is substitutedwith hydroxy.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

The term “fluoro-lower-alkyl” refers to lower-alkyl groups which aremono- or multiply substituted with fluorine. Examples offluoro-lower-alkyl groups are e.g. CFH₂, CF₂H, CF₃, CF₃CH₂, CF₃(CH₂)₂,(CF₃)₂CH and CF₂H—CF₂.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl.

The term “fluoro-lower-alkoxy” refers to the group R″—O—, wherein R″ isfluoro-lower-alkyl. Examples of fluoro-lower-alkoxy groups are e.g.CFH₂—O, CF₂H—O, CF₃—O, CF₃CH₂—O, CF₃(CH₂)₂—O, (CF₃)₂CH—O, andCF₂H—CF₂—O.

The term “acid isostere” refers to groups which have similar steric andelectronic features of a carboxylic acid, or that are known in the artto mimic the spatial arrangement and electronic properties of acarboxylic acid. Examples of acid isosteres are 1H-tetrazol-5-yl,4H-[1,2,4]oxadiazol-3-yl-5-one, 4H-[1,2,4]thiadiazol-3-yl-5-one,4H-[1,2,4]oxadiazol-3-yl-5-thione,3H-[1,2,3,5]oxathiadiazol-4-yl-2-oxide, SO₃H, 3-hydroxy-isooxazol,3-hydroxy-pyran-4-one or P(O)(OCH₂CH₃)OH.

The term “aryl”, alone or in combination, relates to the phenyl ornaphthyl group, preferably the phenyl group, which can optionally besubstituted, unless specifically stated otherwise, by 1 to 5, preferably1 to 3, substituents, independently selected from the group consistingof halogen, hydroxy, amino, NO₂, lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy, carboxy, carboxy-lower-alkyl, H₂NC(O),(H,lower-alkyl)NC(O), (lower-alkyl)₂NC(O), fluoro-lower-alkyl,lower-alkyl-SO₂, lower-alkyl-SO₂O, lower-alkyl-SO₂—NH,lower-alkyl-SO₂—N(lower-alkyl), H₂NSO₂, (H,lower-alkyl)NSO₂,(lower-alkyl)₂NSO₂, cyano, heteroaryl, cycloalkyl, phenyl and phenyloxy.Preferred substituents are halogen, lower-alkyl, fluoro-lower-alkyl,lower-alkoxy and fluoro-lower-alkoxy. Furthermore, aryl groups can besubstituted as described in the description below.

The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclicring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3atoms selected from nitrogen, oxygen and/or sulphur, such as furyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl,oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,benzoimidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzoxazolyl,benzoisoxazolyl and quinolinyl. Preferred heteroaryl groups arepyridinyl, pyrazolyl and thiazolyl, more preferably pyridinyl andthiazolyl. Unless specifically stated otherwise, a heteroaryl group mayoptionally have a substitution pattern as described earlier inconnection with the term “aryl”. Furthermore, heteroaryl groups can besubstituted as described in the description below.

Compounds of formula (I) can form pharmaceutically acceptable salts withbases. Examples of such salts are alkaline, earth-alkaline and ammoniumsalts such as e.g. sodium, potassium, calcium and trimethylammoniumsalt. The term “pharmaceutically acceptable salts” refers to such salts.

The term “pharmaceutically acceptable esters” embraces derivatives ofthe compounds of formula (I), in which a carboxy group has beenconverted to an ester. Lower-alkyl, hydroxy-lower-alkyl,lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- ordi-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl,pyrrolidino-lower-alkyl, piperidino-lower-alkyl, piperazino-lower-alkyl,lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples ofsuitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arepreferred esters. The term “pharmaceutically acceptable esters”furthermore embraces compounds of formula (I) in which hydroxy groupshave been converted to the corresponding esters with inorganic ororganic acids such as, nitric acid, sulphuric acid, phosphoric acid,citric acid, formic acid, maleic acid, acetic acid, succinic acid,tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and thelike, which are non toxic to living organisms.

In detail, the present invention relates to compounds of formula (I)

wherein

V is N or —C(R⁷)—; W is a single bond or —C(R⁸R⁹)—; X is O, S, SO, SO₂or N(R¹⁰); Y is —C(R¹¹R¹²)—, —C(R¹¹R¹²)C(R¹³R¹⁴)—,—C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)—, —C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)C(R¹⁷R¹⁸)— or—C(R¹¹)═C(R¹²)—;

R¹, R², R³, R⁴ and R⁵ independently from each other are hydrogen,halogen, cyano, hydroxy, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy,fluoro-lower-alkoxy, lower-alkyl-C(O), lower-alkyl-C(O)—NH,lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂, NH₂—S(O)₂,N(H,lower-alkyl)-S(O)₂ or N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), COOH or lower-alkoxy-C(O),wherein lower-alkyl is optionally substituted with hydroxy, NH₂,N(H,lower-alkyl) or N(lower-alkyl)₂;R⁶ is an aryl or heteroaryl group, which aryl or heteroaryl group isoptionally substituted by 1 to 4 substituents selected from the groupconsisting of halogen, hydroxy, cyano, lower-alkyl, fluoro-lower-alkyl,lower-alkoxy, fluoro-lower-alkoxy, lower-alkyl-C(O),lower-alkyl-C(O)—NH, lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂,NH₂—S(O)₂, N(H,lower-alkyl)-S(O)₂, N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), lower-alkoxy-C(O), COOH,1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl,5-oxo-4H-[1,2,4]thiadiazol-3-yl, 5-thioxo-4H-[1,2,4]oxadiazol-3-yl,2-oxo-3H-[1,2,3,5]oxathiadiazol-4-yl, SO₃H, 3-hydroxy-isooxazol-5-yl,6-oxo-6H-pyran-3-yl, 6-oxo-6H-pyran-2-yl, 2-oxo-2H-pyran-3-yl,2-oxo-2H-pyran-4-yl and P(O)(OCH₂CH₃)OH, wherein lower-alkyl isoptionally substituted with COOH, hydroxy, NH₂, N(H,lower-alkyl) orN(lower-alkyl)₂, and wherein fluoro-lower-alkyl is optionallysubstituted with hydroxy;

R⁷ is hydrogen, halogen, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl,fluoro-lower-alkoxy, hydroxy or hydroxy-lower-alkyl; R⁸ and R⁹independently from each other are hydrogen or lower-alkyl; R¹⁰ ishydrogen, lower-alkyl, cycloalkyl, lower-alkyl-C(O), lower-alkyl-S(O)₂,lower-alkoxy-C(O), (lower-alkyl)NH—C(O), or (lower-alkyl)₂N—C(O); R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ independently from each other arehydrogen, halogen, hydroxy, lower alkyl, lower-alkoxy,fluoro-lower-alkyl, fluoro-lower-alkoxy, hydroxy-lower-alkyl, aryl,COOH, C(O)O-lower-alkyl or cyano;

and pharmaceutically acceptable salts and esters thereof.

Compounds of formula (I) are individually preferred and physiologicallyacceptable salts thereof are individually preferred and pharmaceuticallyacceptable esters thereof are individually preferred, with the compoundsof formula (I) being particularly preferred.

The compounds of formula (I) can have one or more asymmetric C or Satoms and can therefore exist as an enantiomeric mixture, mixture ofstereoisomers or as optically pure compounds.

Preferred compounds of formula (I) as defined above are those, whereinR¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ independently from each otherare hydrogen, halogen, hydroxy, lower alkyl, lower-alkoxy,fluoro-lower-alkyl, fluoro-lower-alkoxy, hydroxy-lower-alkyl, aryl orcyano. In the compounds as described above, such in which V is N areindividually preferred and such wherein V is —C(R⁷)— are individuallypreferred. Compounds wherein V is —C(R⁷)— and R⁷ is as defined above areparticularly preferred. Preferably, W is a single bond.

A preferred embodiment of the present invention relates to compounds asdescribed above, wherein X is O, S, SO₂ or N(R¹⁰) and R¹⁰ is as definedabove. Compounds wherein X is O are individually preferred, compoundswherein X is S are individually preferred, compounds wherein X is SO areindividually preferred, compounds wherein X is SO₂ are individuallypreferred and compounds wherein X is N(R¹⁰) and R¹⁰ is as defined aboveare individually preferred.

Other preferred compounds according to the present invention are those,wherein Y is —C(R¹¹R¹²)— or —C(R¹¹R¹²)C(R¹³R¹⁴)—, and R¹¹, R¹², R¹³ andR¹⁴ are as defined above.

Furthermore, those compounds are preferred, wherein R¹, R², R³, R⁴ andR⁵ independently from each other are hydrogen, halogen, lower-alkyl,fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy or NH₂—C(O).Preferably at least 2 of R¹, R², R³, R⁴ and R⁵ are hydrogen, morepreferably at least 3, even more preferably at least 4. Preferably, R¹,R², R³, R⁴ and R⁵ independently from each other are hydrogen, halogen orlower-alkoxy. Preferably, R¹ is lower-alkoxy, more preferably R¹ ismethoxy. It is preferred, that R², R³ and R⁵ are hydrogen. It is alsopreferred that R⁴ is halogen, more preferably R⁴ is chloro.

Another preferred embodiment of the present invention is related tocompounds of formula (I) as defined above, wherein R⁶ is an aryl orheteroaryl group, which aryl or heteroaryl group is optionallysubstituted by 1 to 4 substituents selected from the group consisting ofhalogen, cyano, lower-alkyl, carboxy-lower-alkyl, lower-alkoxy, COOH,1H-tetrazol-5-yl and 5-oxo-4H-[1,2,4]oxadiazol-3-yl. Preferably, R⁶ isan aryl or heteroaryl group, which aryl or heteroaryl group isoptionally substituted by 1 to 4 substituents selected from the groupconsisting of halogen, lower-alkyl, carboxy-lower-alkyl, lower-alkoxy,COOH, 1H-tetrazol-5-yl and 5-oxo-4H-[1,2,4]oxadiazol-3-yl. Morepreferably, R⁶ is a phenyl, pyridinyl, pyrazolyl or thiazolyl group,which group is optionally substituted by 1 to 2 substituents selectedfrom the group consisting of halogen, cyano, lower-alkyl,carboxy-lower-alkyl, lower-alkoxy, COOH, 1H-tetrazol-5-yl and5-oxo-4H-[1,2,4]oxadiazol-3-yl. More preferably, R⁶ is a phenyl,pyridinyl or thiazolyl group, which group is optionally substituted by 1to 2 substituents selected from the group consisting of halogen,lower-alkyl, carboxy-lower-alkyl, lower-alkoxy, COOH, 1H-tetrazol-5-yland 5-oxo-4H-[1,2,4]oxadiazol-3-yl. More preferably, R⁶ is a phenyl,pyridinyl or thiazolyl group, which group is optionally substituted by 1to 2 substituents selected from the group consisting of halogen,carboxy-lower-alkyl and COOH, more preferably halogen and COOH. Mostpreferably, R⁶ is 4-carboxy-phenyl, 3-fluoro-4-carboxy-phenyl,3-chloro-4-carboxy-phenyl, 2-carboxy-pyridin-5-yl,4-carboxy-methyl-phenyl, 4-carboxy-methyl-thiazol-2-yl or2-carboxy-methyl-thiazol-4-yl.

Other preferred compounds of the present invention are those, wherein R⁷is hydrogen, halogen, lower-alkyl, lower-alkoxy or fluoro-lower-alkoxy.Preferably, R⁷ is hydrogen or halogen. More preferably, R⁷ is hydrogenor fluoro. Furthermore, it is preferred that R⁸ and R⁹ are hydrogen. Itis also preferred that R¹⁰ is hydrogen.

Other preferred compounds according to the present invention are those,wherein R¹¹, R¹²R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ independently from eachother are hydrogen or phenyl. More preferably, R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷ and R¹⁸ are hydrogen. Furthermore, it is preferred that R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are hydrogen, COOH orC(O)O-lower-alkyl. Preferably, not more than one of R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is phenyl, COOH or C(O)O-lower-alkyl.

In particular, preferred compounds are the compounds of formula (I)described in the examples as individual compounds as well aspharmaceutically acceptable salts as well as pharmaceutically acceptableesters thereof.

Preferred compounds of formula (I) are those selected from the groupconsisting of:

-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-3-methyl-benzoic    acid,-   2-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic    acid [4-(1H-tetrazol-5-yl)-phenyl]-amide,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic    acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino)-benzoic    acid,-   5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-pyridine-2-carboxylic    acid,-   4-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino{-benzoic    acid,-   4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-benzoic    acid,-   4-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   2-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   2-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-2-fluoro-benzoic    acid,-   2-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   6-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinic    acid,-   2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino)-benzoic    acid,-   4-[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino)-2-fluoro-benzoic    acid,-   3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic    acid phenylamide,-   3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic    acid pyridin-3-ylamide,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[9-(5-Chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoic    acid,-   4-{[6-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[7-Chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[8-Chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic    acid (4-fluoro-phenyl)-amide,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoic    acid,-   1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic    acid phenylamide,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylic    acid phenylamide,-   (2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-acetic    acid,-   (4-[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic    acid phenylamide,-   3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-benzoic    acid,-   (2-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-thiazol-4-yl)-acetic    acid, and-   (4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-phenyl)-acetic    acid,    and pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds of formula (I) are those selected fromthe group consisting of:

-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic    acid,-   4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   (2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid, and-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,    and pharmaceutically acceptable salts and esters thereof.

Other preferred compounds of formula (I) are those selected from thegroup consisting of:

-   2-Chloro-5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-5-yl)-acetic    acid,-   2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-5-carboxylic    acid,-   (3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   3-(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-propionic    acid,-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-5-methyl-thiazol-4-yl)-acetic    acid,-   (3-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyrazol-1-yl)-acetic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoic    acid,-   2-Fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic    acid,-   (2-{[4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (2-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (2-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid,-   (3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-pyrazol-1-yl)-acetic    acid,-   4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3-Chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3-Chloro-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3,5-Dimethyl-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(3,5-Dimethyl-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-acetic    acid,-   4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   4-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoic    acid,-   2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid ethyl ester,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid ethyl ester,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid ethyl ester,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid,-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid ethyl ester, and-   4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic    acid    and pharmaceutically acceptable salts and esters thereof.

Other particularly preferred compounds of formula (I) are those selectedfrom the group consisting of:

-   (2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic    acid, and-   (4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-acetic    acid    and pharmaceutically acceptable salts and esters thereof.

It will be appreciated that the compounds of general formula (I) in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

The invention further relates to a process for the manufacture ofcompounds of formula (I) as defined above, which process comprisesreacting a compound of formula (XIV)

with a compound of formula (XV)

orreacting a compound of formula (XVI)

with a compound R⁶—NH₂,wherein R¹, R², R³, R⁴, R⁵, R⁶, V, W, X and Y are as defined above.

The reaction of a compound of formula (XIV) with a compound of formula(XV) can be carried out under conditions well known to the personskilled in the art. Such reactions of a compound of formula (XIV) canconveniently be carried out for example by mixing a compound of formula(XIV) with a compound of formula (XV) in anhydrous solvents such as e.g.dichloromethane, tetrahydrofuran, acetonitrile, toluene and mixturesthereof at appropriate temperatures between 0° C. and 110° C.,optionally in the presence of a base, as for example triethylamine,diisopropylethylamine or pyridine.

The reaction of a compound of formula (XVI) with a compound R⁶—NH₂ canbe carried out under conditions well known to the person skilled in theart. Such reactions can conveniently be carried out for example bymixing a compound of formula (XVI) with a compound R⁶—NH₂ in aproticsolvents such as dichloromethane, tetrahydrofuran,N,N-dimethylformamide, N-methylpyrrolidinone and mixtures thereof attemperatures between 0° C. and 60° C. in the presence or absence of abase such as triethylamine or N,N-diisopropylethylamine, and acondensing agent. Appropriate condensing agents can be for exampleO-(7-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate(TBTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexaflurophophate(HATU), N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,bromo-tris-pyrrolidino-phosphonium hexafluorophosphate or others wellknown to the person skilled in the art. Alternatively, such reactionscan be performed in two steps involving first formation of the acylhalide derivative of the compound of formula (XVI) and subsequentcoupling reaction with an amine R⁶—NH₂ in the presence of a base.Typically employed reagents for the formation of the acyl chloride arethionyl chloride, phosphorous pentachloride, oxalyl chloride or cyanuricchloride, and the reaction is generally conducted in the absence of asolvent or in the presence of an aprotic solvent like dichloromethane,toluene or acetone. A base can optionally be added, like for examplepyridine, triethylamine, diisopropyl ethyl amine or N-methyl morpholine.The obtained acyl chloride can be isolated or reacted as such with anappropriate amine R⁶—NH₂ in an aprotic solvent, like dichloromethane,tetrahydrofuran or acetone, in the presence of a base. Typical bases aretriethylamine, 4-methylmorpholine, pyridine, diisopropyl ethyl amine ordimethylaminopyridine or mixtures thereof.

The present invention also relates to compounds of formula (I) asdefined above, when prepared by a process as described above.

The compounds of formula (I), (XIV), (XV), (XVI) and R⁶—NH₂ can beprepared by methods known in the art or as described below or in analogythereto. Unless otherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, V, W, X andY are as described above.

Compounds of formula I, wherein V is C—R⁷, W is a single bond, X is Oand Y is —C(R¹¹R¹²)C(R¹³R¹⁴)— are part of the present invention and canbe represented by formula II:

Compounds of general formula II can be accessed according to thefollowing general scheme 1:

In step 1, scheme 1, a 4-hydroxy-3-nitro-benzoic acid alkyl ester 1(R^(a)=lower alkyl, e.g., methyl or ethyl) is converted to thecorresponding amine 2 using methods well known to those skilled in theart, e.g. nitro reduction. The reaction is typically carried out insolvents such as ethanol, methanol, water under an atmosphere ofhydrogen at a pressure of 1 to 50 bar and temperatures between 0° C. and100° C. with catalysts such as palladium, platinum or platinum oxide.Alternatively, the reaction can be carried out using reducing metalslike for example tin or tin chloride in the presence of concentratedmineral acids like hydrochloric or sulfuric acid, or with Ni/Raney.

In step 2, scheme 1, aminophenol 2 is converted to the corresponding3,4-dihydro-2H-benzo[1,4]oxazine 3 using methods well known to thoseskilled in the art, e.g. double nucleophilic substitution with anappropriately substituted 1,2-dibromoethane or1,2-bis(alkyl-/aryl-sulfonyloxy)-ethane derivative. The reaction istypically carried out in an aprotic solvent like dimethylformamide,acetone, tetrahydrofuran in the presence of a base like for examplepotassium carbonate, sodium carbonate or cesium carbonate attemperatures between 0° C. and 100° C.

In step 3, scheme 1, the obtained compound of general formula 3 isconverted into the sulfonamide analogue of general formula 4, usingmethods well known to someone skilled in the art, e.g. sulfonylation ofamines with sulfonyl chlorides. The reaction is typically carried out insolvents such as dichloromethane, tetrahydrofuran, acetonitrile,toluene, pyridine, triethylamine, or mixtures thereof, at temperaturesbetween 0° C. and 110° C.

In step 4, scheme 1, the 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid alkyl ester 4 is converted into the corresponding carboxylic acidof the formula 5, using methods well known to someone skilled in theart, e.g. base mediated ester hydrolysis. The reaction is typicallycarried out in solvents such as water, methanol, ethanol,tetrahydrofuran and mixtures thereof at temperatures between −20° C. and120° C. Typical reagents are aqueous or anhydrous lithium hydroxide,lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide,sodium hydrogen carbonate, sodium carbonate, potassium hydrogencarbonate and potassium carbonate.

In step 5, scheme 1, the carboxylic acid derivative of the formula 5 isconverted, with the appropriate amine R⁶—NH₂, into the correspondingamide of general formula II, using methods well known to someone skilledin the art e.g. amide formation using a coupling reagent. The reactionis typically carried out in aprotic solvents such as dichloromethane,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidinone andmixtures thereof at temperatures between 0° C. and 80° C. in thepresence or absence of a base such as triethylamine,diisopropylethylamine, 4-methylmorpholine, and/or4-(dimethylamino)pyridine. Typically used coupling agents areN,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate and bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate. Alternatively, such reaction can be performed intwo steps involving first formation of the acyl halide derivative of 4and subsequent coupling reaction with an appropriate amine in thepresence of a base. Typically employed reagents for the formation of theacyl chloride are thionyl chloride, phosphorous pentachloride, oxalylchloride or cyanuric chloride, and the reaction is generally conductedin the absence of a solvent or in the presence of an aprotic solventlike dichloromethane, toluene or acetone. A base can optionally beadded, like for example pyridine, triethylamine, diisopropylethylamineor 4-methylmorpholine. The obtained acyl chloride can be isolated orreacted as such with amine R⁶—NH₂ in an aprotic solvent, likedichloromethane, tetrahydrofuran or acetone, in the presence of a base.Typical bases are triethylamine, 4-methylmorpholine, pyridine,diisopropylethylamine or 4-(dimethylamino)pyridine or mixtures thereof.

Alternatively, compounds of general formula II can be prepared asillustrated in the general scheme 2:

In step 1, scheme 2, the 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid alkyl ester 3 is converted into the correspondingtert-butylcarbamate of formula 6, using methods well known to someoneskilled in the art, e.g. tert-butylcarbamate protection under basicconditions. The reaction is typically carried out in aprotic solventssuch as acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide,N-methylpyrrolidinone, dioxane and mixtures thereof at temperaturesbetween 20° C. and 100° C. Typically used bases are sodium hydride,potassium hydride, sodium methoxide, potassium tert-butoxide,triethylamine, N,N-diisopropylethylamine, pyridine and potassiumcarbonate.

In step 2, scheme 2, the obtained compound of the formula 6 is convertedinto the corresponding carboxylic acid of the formula 7, in analogy withscheme 1, step 4.

In step 3, scheme 2, the carboxylic acid derivative of formula 7 isconverted, with the appropriate amine R⁶—NH₂, into the correspondingamide 8, in analogy with scheme 1, step 5.

In step 4, scheme 2, the tert-butylcarbamate group is removed to give acompound of formula 9, using methods well known to someone skilled inthe art, e.g. acid mediated tert-butylcarbamate deprotection. This istypically carried out with or without solvents such as dichloromethane,dioxane and tetrahydrofuran and mixtures thereof at temperature between0° C. and 60° C. Typically used acids are hydrogen chloride,concentrated hydrochloric acid and trifluoroacetic acid.

In step 5, scheme 2, the obtained compounds of general formula 9 areconverted into their corresponding sulfonamides of general formula II,in analogy to scheme 1, step 3.

Intermediates of general formula 9 can also be prepared as illustratedin the general scheme 3:

In step 1, scheme 3, nitrophenol of general formula 1 is protected witha benzylic group according to methods well known to somebody skilled inthe art, i.e. phenol alkylation. The reaction is typically carried outin an aprotic solvent such as tetrahydrofuran, dimethylformamide,acetone at temperatures between −20° C. and 120° C. using benzyl bromideor benzyl chloride. Typically used bases are potassium tert-butoxide,potassium carbonate, sodium hydride and the like.

In step 2, scheme 3, ester 10 is converted to the correspondingcarboxylic acid 11, in analogy with scheme 1, step 4.

In step 3, scheme 3, the obtained acid of general formula 11 isconverted to the corresponding acyl chloride 12 using methods well knownto someone skilled in the art. Typically employed reagents for theformation of the acyl chloride are thionyl chloride, phosphorouspentachloride, oxalyl chloride or cyanuric chloride, and the reaction isgenerally conducted in the absence of a solvent or in the presence of anaprotic solvent like dichloromethane, toluene, dimethylformamide,acetone or mixtures thereof. A base can optionally be added, like forexample pyridine, triethylamine, diisopropylethylamine or N-methylmorpholine.

In step 4, scheme 3, acyl chloride 12 is coupled with an appropriateamine R⁶—NH₂ to form the corresponding amide 13. The reaction istypically carried out in an aprotic solvent, like dichloromethane,tetrahydrofuran or acetone, in the presence of a base. Typical bases aretriethylamine, 4-methylmorpholine, pyridine, diisopropylethylamine ordimethylaminopyridine or mixtures thereof.

In step 5, scheme 3, the benzyl group of the obtained compound 13 iscleaved and at the same time the nitro group is reduced to produce thecorresponding aminophenol 14 using methods well known to someone skilledin the art, e.g. reductive debenzylation and nitro reduction. Thereaction is typically carried out in a solvent like methanol, ethanol,dichloromethane, tetrahydrofuran, dimethylformamide, water or mixturesthereof at temperature between 20° C. and 60° C. under an atmosphere ofhydrogen at pressure between 1 and 50 bar. Typically used catalysts arepalladium, platinum, platinum oxide and the like.

In step 6, scheme 3, the obtained aminophenol of general formula 14 isconverted to the corresponding 3,4-dihydro-2H-benzo[1,4]oxazine 9, inanalogy with scheme 1, step 2.

Intermediates of general formula 4 can also be prepared as illustratedin the general scheme 4:

In step 1, scheme 4, 3-amino-4-hydroxybenzoate 2 is converted to thesulfonamide of general formula 15, in analogy with scheme 1, step 3.

In step 2, scheme 4, compound 15 is cyclized with an appropriatelysubstituted 1,2-dibromo-ethane reagent to produce 4, in analogy withscheme 1, step 2.

Compounds of formula I wherein V is C—R⁷, W is a single bond, X is O andY=—C(R¹¹)═C(R¹²)— are part of the present invention and can berepresented by formula III:

Compounds of general formula III can be accessed according to thefollowing general scheme 5:

In step 1, scheme 5, compound 15 is transformed into diallyl derivative16, using methods well known to somebody skilled in the art. Forinstance, the reaction is performed with an allyl halide derivative, ina solvent such as acetone, acetonitrile, or N,N-dimethylformamide, inthe presence of a base, e.g., sodium carbonate, potassium carbonate, orsodium hydride, at temperatures between 20° C. and 100° C.Alternatively, 16 is prepared from 15 under Mitsunobu conditions usingan allyl alcohol derivative, a phosphine, e.g., triphenylphosphine, anazodicarboxylate, e.g., diethyl azodicarboxylate or diisopropylazodicarboxylate, in a solvent such as dichloromethane, toluene ortetrahydrofuran and at temperatures between 0° C. and 40° C.

In step 2, scheme 5, the bis-allyl compound 16 is converted into 17 inthe presence a suitable alkene isomerization catalyst e.g.,carbonylchlorohydrotris(triphenylphosphine)ruthenium. The reaction iscarried out in an inert solvent such as toluene or xylene, attemperatures between 20° C. and the boiling point of the solvent.

In step 3, scheme 5, compound 17 is transformed into benzo[1,4]oxazinederivative 18 by a ring-closing metathesis reaction, in the presence ofa suitable catalysts. Several catalysts capable of promoting thisreaction are known in the literature, e.g.,benzylidenedichlorobis(tricyclohexyl-phosphine)ruthenium; ordichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenyl-methylene)(tricyclohexylphosphine)ruthenium. The reaction iscarried out in an inert solvent such as toluene or dichloromethane, attemperatures between 20° C. and the boiling point of the solvent.

The preparation of the benzo[1,4]oxazines of general formula III fromintermediate 18 follows the same synthetic route as that described inthe preparation of 3,4-dihydro-2H-benzo[1,4]oxazines of general formulaII from the intermediate 4 (scheme 1, steps 4 and 5).

Compounds of formula I wherein V is C—R⁷, W is a single bond, X is O andY=—C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)— are part of the present invention andcan be represented by formula IV:

Compounds of general formula IV can be prepared in analogy to compoundsof general formula II (schemes 1-4), but by replacing the1,2-dibromoethane derivative in the cyclisation step with anappropriately substituted 1,3-dibromopropane derivative.

Compounds of formula I wherein V is C—R⁷, W is a single bond, X is O andY=—C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)C(R¹⁷R¹⁸)— are part of the presentinvention and can be represented by formula V:

Compounds of general formula V can be produced in analogy to compoundsof general formula II (schemes 1-4), but by replacing the1,2-dibromoethane derivative in the cyclisation step with anappropriately substituted 1,4-dibromobutane derivative.

Compounds of formula I wherein V is C—R⁷, W is a single bond, X is O andY=—C(R¹¹R¹²)— are part of the present invention and can be representedby formula VI:

Compounds of general formula VI can be synthesized according to scheme6:

In step 1, scheme 6, N-(2-hydroxy-phenyl)-benzenesulfonamide derivative15 is converted to N-phenylsulfonyl-2,3-dihydro-benzoxazole 19 accordingto methods well known to somebody skilled in the art, e.g., doublenucleophilic substitution or acetalization. For instance, 15 is reactedwith dibromomethane in the presence of a base, e.g., sodium carbonate,potassium carbonate, or sodium hydride, in a solvent such asacetonitrile or N,N-dimethylformamide at temperatures between 60° C. and100° C. Alternatively, and especially preferred in the case where R¹¹and/or R¹²≠H, 15 is reacted with an suitable free or masked carbonylderivative such as aldehyde, ketone or acetal, in the presence of acatalyst, e.g., toluene-4-sulfonic acid, titanium(IV)chloride or zincchloride, optionally in the presence of a solvent, such as toluene ordichloromethane, at temperatures between 0° C. and 150° C.

The preparation of the 2,3-dihydro-benzoxazoles of general formula VIfrom intermediate 19 follows the same synthetic route as that describedin the preparation of 3,4-dihydro-2H-benzo[1,4]oxazines of generalformula II from the intermediate 4 (scheme 1, steps 4 and 5).

Compounds of formula I wherein W is a single bond, X′=NH, N-alkyl, orN-cycloalkyl, or S, and Y=—CH₂C(R¹³R¹⁴)—, are part of the presentinvention and can be represented by formula VII:

Compounds of general formula VII can be accessed according to thegeneral scheme 7:

In step 1, scheme 7, 1-nitro-2,5-halo-arene 20 (Hal=Br, I; Hal′=F, Cl,Br, I) is transformed into compound 21, using methods well known in theart. The reaction is performed with an appropriate reagent(H—X′—C(R¹³R¹⁴)—C(O)—O—R^(a), with R^(a)=methyl or ethyl), optionally inthe presence of a base, e.g., sodium hydride, sodium hydroxide,potassium hydroxide, potassium carbonate, sodium carbonate, sodiumhydrogencarbonate, in a solvent such as tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, or dimethyl sulfoxide, at a temperature between20° C. and 200° C., optionally under microwave irradiation.

In step 2, scheme 7, compound 21 is elaborated into lactam 22 throughmethods known in the art, i.e., reduction of the nitro group andsimultaneous cyclisation. The reaction is performed using a reducingmetal such as iron or tin, in a suitable solvent, e.g., methanol,ethanol, acetic acid, or water, optionally in the presence of an acid,e.g., hydrochloric acid or sulfuric acid, at temperatures between 20° C.and the boiling point of the solvent.

In step 3, scheme 7, the amide group of 22 is reduced to produce thecorresponding amine 23. This reaction is accomplished using a suitablereagent, e.g., borane-tetrahydrofuran complex, borane-dimethylsulfidecomplex, diisobutylaluminum hydride, or lithium aluminum hydride, in asolvent such as tetrahydrofuran, at temperatures between 0° C. and 50°C.

In step 4, scheme 7, amine 23 is converted to the sulfonamide of generalformula 24, in analogy with scheme 1, step 3.

In step 5, scheme 7, halide 24 is converted to the carboxylic acid alkylester 25 using methods well known to somebody skilled in the art, i.e.palladium-catalyzed alkoxycarbonylation. The reaction is typicallycarried out in an alcoholic solvent such as methanol or ethanol, or in amixture of an alcoholic solvent with an aprotic solvent, like toluene orethyl acetate, at temperatures between 25° C. and 150° C. under anatmosphere of carbon monoxide at pressures between 1 bar and 100 bar,and in the presence of a base, e.g., triethylamine or4-methylmorpholine. Typically used palladium catalysts are palladiumdichloride, palladium tetrakis(triphenylphosphine) ordichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium.

The preparation of the compounds of general formula VII fromintermediate 25 follows the same synthetic route as that described inthe preparation of 3,4-dihydro-2H-benzo[1,4]oxazines of general formulaII from the intermediate 4 (scheme 1, steps 4 and 5).

Intermediates of general formula 25 can be also prepared starting fromcompounds of general formula 26 (R^(a)=methyl or ethyl), according toscheme 8:

In step 1, scheme 8, 26 is reacted at the hydroxy, amino or thiol groupto afford 27, applying methods well known in the art, e.g., Williamsonalkylation. The reaction is performed with an appropriate reagent(Hal-C(R¹³R¹⁴)—C(O)—O—R^(a), with R^(a)=methyl or ethyl, and Hal=Cl, Bror I), in the presence of a base, e.g., sodium hydride, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium hydrogencarbonate, in a solvent such as tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, or dimethyl sulfoxide, at atemperature between 20° C. and 150° C.

In step 2, scheme 8, compound 27 is elaborated into lactam 28, inanalogy to scheme 7, step 2.

In step 3, scheme 8, the amide group of 28 is reduced to the amine,using a suitable reagent, e.g., borane-tetrahydrofuran complex orborane-dimethylsulfide complex. The reaction is performed in a solventsuch as tetrahydrofuran, at temperatures of 0-60° C.

In step 4, scheme 8, amine 29 is converted to sulfonamide 25 in analogyto scheme 7, step 4.

Compounds of formula I wherein V is N, W is a single bond, and X is Oare part of the present invention and can be represented by formulaVIII:

In step 1, scheme 9, the nitro group of 5-halo-2-hydroxy-3-nitropyridine30 (Hal=Br, I) is reduced to the amino group, using methods well knownto somebody skilled in the art. The reaction is typically carried outusing reducing metals like iron or tin, in a solvent such as methanol,ethanol, acetic acid, water, or mixtures thereof, optionally in thepresence of an acid such as ammonium chloride, hydrochloric acid, orsulfuric acid, at temperatures of 20-100° C.

In step 2, scheme 9, aminopyridine 31 is converted to sulfonamide 32, inanalogy to scheme 1, step 3.

In step 3, scheme 9, 32 is transformed into 33 by an appropriate method,e.g., double nucleophilic substitution, with an appropriatelysubstituted α,ω-dibromoalkane or α,ω-bis-(alkyl-/aryl-sulfonyloxy)alkanederivative. The reaction is typically carried out in an aprotic solventlike dimethylformamide, acetone, or tetrahydrofuran in the presence of abase like for example sodium hydride or potassium carbonate, attemperatures between 20° C. and 100° C. Alternatively, and especiallypreferred in the case where Y=C(R¹¹R¹²), with R¹¹ and/or R¹²≠H, 32 isreacted with a suitable free or masked carbonyl derivative such asaldehyde, ketone or acetal, in the presence of a catalyst, e.g.,toluene-4-sulfonic acid, titanium(IV) chloride or zinc chloride,optionally in the presence of a solvent, such as toluene ordichloromethane, at temperatures between 0° C. and 150° C.

Alternatively, steps 2 and 3 can be performed in reverse order.

In step 4, scheme 9, halide 33 is converted into ester 34, in analogy toscheme 7, step 5.

The preparation of the compounds of general formula VIII fromintermediate 34 follows the same synthetic route as that described inthe preparation of 3,4-dihydro-2H-benzo[1,4]oxazines of general formulaII from the intermediate 4 (scheme 1, steps 4 and 5).

Alternatively, compounds of general formula VIII can be obtaineddirectly from halide 33 through palladium-catalyzed aminocarbonylation,using reagents and conditions described in the art. The reactionrequires an appropriately substituted amine, R⁶—NH₂, and is typicallyperformed in an aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide or tetrahydrofuran, at temperatures between 60° C.and 200° C. under an atmosphere of carbon monoxide at pressures between1 bar and 100 bar, or in the presence of a reagent capable of liberatingcarbon monoxide such as molybdenum hexacarbonyl, and in the presence ofa base, e.g., triethylamine, 4-methylmorpholine, or1,8-diazabicyclo[5.4.0]undec-7-ene. Typically used palladium catalystsare palladium dichloride, palladium tetrakis(triphenylphosphine),dichloro[11,1′-bis(diphenylphosphino)ferrocene]palladium, ortrans-bis(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II).Optionally, additional phosphine ligands such as triphenylphosphine,tris(tert-butyl)phosphine tetrafluoroborate, or2,2′-bis(diphenylphosphino)-1,1′-binaphthyl are used.

Compounds of formula I wherein W=—C(R⁸R⁹)— and X is O are part of thepresent invention and can be represented by formula IX:

Compounds of general formula IX can be accessed according to scheme 10:

In step 1, scheme 10, 4-halo-2-nitroarene-carboxylic acid 35 (Hal=Br, I)is converted to benzyl alcohol 36, using methods well known in the art.In the case where R⁸=R⁹=H, the reaction is performed using a suitablereducing agent, e.g., borane-tetrahydrofuran, in a solvent such astetrahydrofuran, at temperatures between 0° C. and 50° C. In step 2,scheme 10, the 2-nitrobenzylalcohol is reduced to the aniline 37 by asuitable reducing agent, e.g., iron, tin, or tin chloride, in a solventsuch as methanol, ethanol, acetic acid, water, or mixtures thereof,optionally in the presence of an acid such as ammonium chloride,hydrochloric acid, or sulfuric acid, at temperatures of 20-100° C.

In the case where R⁸ and R⁹=alkyl, the acid 35 is converted into thecorresponding alkyl ester through acid-promoted esterification, usingthe alcohol as solvent, at temperatures between 25° C. and the boilingpoint of the alcohol, in the presence of a mineral acid such ashydrochloric acid or sulfuric acid. The alkyl ester thus obtained isthen reduced at the nitro group as described above, leading to an alkyl2-amino-benzoate, which is treated with a suitable organometallicreagent such as organomagnesium or organolithium compound to produce 37.

In the case where R⁸≠R⁹, the acid 35 is converted into the correspondingN-methoxy-N-methylamide, using reagents methods known in the art. Forinstance, the acid 35 is activated using a suitable reagent, e.g.,methanesulfonyl chloride, thionyl chloride, isobutyl chloroformate, anda base, e.g., triethylamine or 4-methylmorpholine, then the acidchloride or mixed anhydride intermediate obtained is reacted withN,O,dimethylhydroxylamine, in a solvent such as tetra-hydrofuran ordichloromethane, at temperatures between −10° C. and 40° C. In the nextstep, the nitro group is reduced as described above. The obtained2-amino-N-methoxy-N-methylbenzamide intermediate is then reacted withthe appropriate organomagnesium (R⁸—Mg-Hal, with Hal=Cl, Br, I) ororganolithium (R⁸—Li) reagent, to give an alkyl aryl ketone. This ketoneintermediate is transformed into the benzyl alcohol 37 using a suitableorganomagnesium (R⁹—Mg-Hal, with Hal=Cl, Br, I), organolithiumium(R⁹—Li) reagent, or with a hydride reagent such as sodium borohydride(in the case where R⁹=H).

In step 3, scheme 10, amine 37 is converted to the sulfonamide ofgeneral formula 38, in analogy to scheme 1, step 3.

In step 4, scheme 10, the 2-(sulfonylamino)benzylalcohol 38 istransformed into 39 by an appropriate method, e.g., double nucleophilicsubstitution, with an appropriately substituted α,ω-dibromoalkanederivative. The reaction is typically carried out in an aprotic solventlike dimethylformamide, tetrahydrofuran in the presence of a base likefor example sodium hydride or potassium tert-butoxide, at temperaturesbetween 20° C. and 100° C. Alternatively, and especially preferred inthe case where Y═C(R¹¹R¹²), 38 is reacted with a suitable free or maskedcarbonyl derivative such as aldehyde, ketone or acetal, in the presenceof a catalyst, e.g., toluene-4-sulfonic acid, titanium(IV)chloride orzinc chloride, optionally in the presence of a solvent, such as tolueneor dichloromethane, at temperatures between 0° C. and 150° C.

In step 5, scheme 10, halide 39 is converted into ester 40, in analogyto scheme 7, step 5.

The preparation of the compounds of general formula IX from intermediate40 follows the same synthetic route as that described in the preparationof 3,4-dihydro-2H-benzo[1,4]oxazines of general formula II from theintermediate 4 (scheme 1, steps 4 and 5).

Alternatively, intermediates of general formula 40 can be prepared asillustrated in the general scheme 11:

In step 1, scheme 11, 4-(alkoxycarbonyl)-3-amino-arene-carboxylic acid41 (R^(a)=lower alkyl, e.g., methyl or ethyl) is reacted at the esterfunctional group with an appropriate reagent, leading to benzyl alcoholderivative 42. In the case where R⁸ and R⁹=H, this conversion isaccomplished with a borohydride reagent, e.g., lithium borohydride, in asolvent such as tetrahydrofuran. In the case where R⁸ and R⁹=alkyl, 41is reacted with two equivalents of a suitable organolithium ororganomagnesium reagent, in a solvent such as diethyl ether ortetrahydrofuran.

In step 2, scheme 11, carboxylic acid 42 is converted into thecorresponding alkyl ester (R^(a)=lower alkyl) using methods known in theart, e.g., alkylation. This reaction is carried out using suitablereagents, e.g., alkyl halides or sulfonic acid alkyl esters, and a basesuch as potassium hydrogencarbonate or potassium carbonate, in a solventsuch as N,N-dimethylformamide, acetone, or acetonitrile, at temperaturesbetween 0° C. and 80° C.

In step 3, scheme 11, amine 43 is converted to the sulfonamide ofgeneral formula 44, in analogy to scheme 1, step 3.

In step 4, scheme 11, compound 44 is cyclized with appropriate reagents,in analogy to scheme 10, step 5, leading to compound of general formula40.

Compounds of formula I wherein W is a single bond, and X is NR¹⁰ arepart of the present invention and can be represented by formula X:

Compounds of general formula X can be accessed according to the generalscheme 12:

In step 1, scheme 12, the 4-amino-3-nitro-arenecarboxylic acid 45 isconverted to the corresponding alkyl ester 46 (R^(a)=methyl or ethyl)according to methods well known to somebody skilled in the art, e.g.acid promoted esterification. The reaction is typically carried out inthe alcohol as solvent at temperatures between 25° C. and 100° C. in thepresence of a mineral acid like for example hydrochloric or sulfuricacid.

In step 2, scheme 12, the obtained compounds of formula 46 are convertedinto the corresponding tert-butylcarbamate of formula 47, using methodswell known to someone skilled in the art, e.g. tert-butylcarbamateprotection under basic conditions. The reaction is typically carried outin aprotic solvents such as acetone, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, N-methylpyrrolidinone, dioxane and mixturesthereof at temperatures between 20° C. and 100° C.

Typically used bases are sodium hydride, potassium hydride, sodiummethoxide, potassium tert-butoxide, triethylamine,N,N-diisopropylethylamine, pyridine and potassium carbonate. Undercertain of these conditions, variable amount of di-tert-butylcarbamatescan be formed, which can be reconverted to the mono-tert-butylcarbamatesusing methods well known to somebody skilled in the art, e.g. acidpromoted tert-butylcarbamate deprotection. The reaction is typicallycarried out with or without solvents such as dichloromethane, dioxaneand tetrahydrofuran and mixtures thereof at temperature between −20° C.and 20° C. Typically used acids are hydrogen chloride, concentratedhydrochloric acid and trifluoroacetic acid.

In step 3, scheme 12, the obtained compounds of general formula 47 areconverted to the corresponding amines 48 using methods well known tothose skilled in the art, e.g. nitro reduction. The reaction istypically carried out in solvents such as ethanol, methanol or waterunder an atmosphere of hydrogen at a pressure of 1 to 50 bar andtemperatures between 0° C. and 100° C. with catalysts such as palladium,platinum or platinum oxide. Alternatively, the reaction can be carriedout using reducing metals like for example tin or tin chloride in thepresence of concentrated mineral acids like hydrochloric or sulfuricacid, or with Ni/Raney.

In step 4, scheme 12, the obtained amine of formula 48 is cyclized tocompound 49, in analogy to scheme 9, step 3.

In step 5, scheme 12, amine 49 is converted into the sulfonamidederivative 50, in analogy to scheme 1, step 3.

The preparation of the amides of general formula 51 from esters offormula 50 follows the same synthetic route as that described in thepreparation of 3,4-dihydro-2H-benzo[1,4]oxazines of general formula IIfrom the intermediate 4 (scheme 1, steps 4 and 5).

In step 8, scheme 12, the tert-butylcarbamate group is removed to givethe compounds of formula 52, using methods well known to someone skilledin the art, e.g. acid mediated tert-butylcarbamate deprotection. This istypically carried out with or without solvents such as dichloromethane,dioxane and tetrahydrofuran and mixtures thereof at temperature between0° C. and 60° C. Typically used acids are hydrogen chloride,concentrated hydrochloric acid and trifluoroacetic acid.

In step 9, scheme 12, the free amine group of compounds of the generalformula 52 can be functionalized to give the compounds of generalformula X in a variety of ways well known to somebody skilled in theart, e.g. alkylation, acylation, reductive alkylation, sulfonylation,formation of carbamates and formation of ureas.

Compounds of general formula I wherein W is a bond X is SO₂, andY=—CH₂C(R¹³R¹⁴)— are part of the present invention and are representedby the general formula XI.

Compounds of general formula XI can be prepared for example startingfrom sulfides of general formula XII, as illustrated in scheme 13.

Sulfides XII, which are prepared as illustrated in schemes 7 and 8, canbe converted to sulfones of general formula XI through reaction with anappropriate oxidizing agent. For instance, XII is treated with at leasttwo equivalents of a peroxide or peracid such as hydrogen peroxide or3-chloroperbenzoic acid, in a solvent such as dichloromethane, water,formic acid or mixtures thereof, at temperatures between 0° C. and 25°C., preferably 0° C. This conversion may also be accomplished on anysynthetic precursor of XII containing the alkyl-aryl-sulfide moiety.

Compounds of general formula I wherein W is a bond, X is SO, andY=—CH₂C(R¹³R¹⁴)— are part of the present invention and are representedby the general formula XIII.

Compounds of general formula XIII can be prepared for example startingfrom sulfides of general formula XII, as illustrated in scheme 14.

Sulfides XII can be converted to sulfoxides of general formula XIIIthrough reaction with an appropriate oxidizing agent. For instance, XIIis treated with one equivalent of a peroxide or peracid such as hydrogenperoxide or 3-chloroperbenzoic acid, in a solvent such asdichloromethane, water, formic acid or mixtures thereof, at temperaturesbetween 0° C. and 25° C., preferably 0° C. This conversion may also beaccomplished on any synthetic precursor of XII containing thealkyl-aryl-sulfide moiety.

Compounds which carry a COOH group, e.g. as a substituent on R⁶, can beprepared from the corresponding esters, e.g. the lower-alkyl esters(e.g. the methyl, ethyl, propyl or tert-butyl esters). Such esters areobtained as described in schemes 1-14 by employing an appropriate(alkoxycarbonylmethyl)-arylamine in the amide formation step.Alternatively, the esters are obtained as described in schemes 1-14 byemploying an appropriate 4-bromoaniline or 4-iodoaniline derivative inthe amide formation step and subjecting the N-4-halophenylamidederivative to a palladium-catalyzed alkoxycarbonylation, in analogy withscheme 7, step 5.

The esters are converted into their corresponding carboxylic acids usingmethods well known to someone skilled in the art, e.g. base oracid-mediated ester hydrolysis.

Base-mediated ester hydrolysis (preferred for methyl, ethyl, propylesters) is typically carried out in solvents such as water, methanol,tetrahydrofuran and mixtures thereof at temperatures between −20° C. and120° C. Typical reagents are aqueous or anhydrous lithium hydroxide,lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide,sodium hydrogen carbonate, sodium carbonate, potassium hydrogencarbonate and potassium carbonate.

Acid-mediated ester hydrolysis (preferred for tert-butyl esters) istypically carried out in liquids such as formic acid, aqueous ornon-aqueous hydrogen chloride solutions, or trifluoroacetic acid attemperatures between 0° C. and 100° C. Optionally, co-solvents such asdichloromethane, 1,4-dioxane or water are used.

Compounds which carry an acid isostere such as 1H-tetrazol-5-yl, e.g. asa substituent on R⁶, can be obtained from the corresponding nitrileswhich are converted to the corresponding 1H-tetrazoles using methodswell known to somebody skilled in the art, e.g. dipolar cycloadditionwith azides. The reaction is typically carried out in an aprotic solventlike dimethylformamide, dimethyl sulfoxide, tetrahydrofuran attemperatures between 25° C. and 200° C. using an azide source likeammonium azide, sodium azide or trialkyltin azide. The nitriles can beobtained as described in schemes 1-14 by employing an appropriateamino-cyano-arene in the amide formation step.

Compounds which carry an acid isostere such as5-oxo-4H-[1,2,4]oxadiazol-3-yl, e.g. as a substituent on R⁶, can beobtained as follows. In a first step, the corresponding benzonitrilesare converted to N-hydroxy-benzamidines using methods well known tosomebody skilled in the art, e.g. nucleophilic addition withhydroxylamine. The reaction is typically carried out in an aproticsolvent like dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,acetonitrile, at temperatures between 0° C. and 150° C. in the presenceof a base like triethylamine, diisopropylethylamine, 4-methylmorpholineor pyridine. In a second step, the obtained N-hydroxybenzamidines can beconverted to the desired compounds using methods well known to somebodyskilled in the art, e.g. intramolecular carbamate formation. Thereaction is typically carried out in an aprotic solvent like benzene,toluene, xylene, dimethylformamide, dimethyl sulfoxide or mixturesthereof at temperatures between 0° C. and 200° C. in the presence of abase. Typical reagents for the formation of the carbamates are phosgene,triphosgene, carbonyldiimidazole, chloroformic acid alkyl esters, andthe like. Typical bases are triethylamine, diisopropylethylamine,4-methylmorpholine or pyridine.

Compounds which carry an acid isostere such as2-oxo-3H-[1,2,3,5]oxathiadiazol-4-yl, e.g. as a substituent on R⁶, canbe obtained by starting from the corresponding N-hydroxy-benzamidines.N-Hydroxy-benzamidines can be converted to the desired compounds usingmethods well known to somebody skilled in the art, e.g. intramolecularsulfinamidate formation. The reaction is typically carried out in anaprotic solvent like dimethylformamide, dimethyl sulfoxide,acetonitrile, tetrahydrofuran or dichloromethane or mixtures thereof inthe presence of a base. A typically used reagent is thionyl chloride andtypical bases are triethylamine, diisopropylethylamine,4-methylmorpholine or pyridine.

Compounds which carry an acid isostere such as5-thioxo-4H-[1,2,4]oxadiazol-3-yl, e.g. as a substituent on R⁶, can beobtained by starting from the corresponding N-hydroxy-benzamidines. TheN-Hydroxy-benzamidines can be converted to the desired compounds usingmethods well known to somebody skilled in the art, e.g. intramolecularthiocarbamate formation. The reaction is typically carried out in anaprotic solvent like dimethyl-formamide, dimethyl sulfoxide,acetonitrile, tetrahydrofuran or dichloromethane or mixtures thereof inthe presence of a base. A typically used reagent is1,1′-thiocarbonyl-diimidazole and typical bases are triethylamine,diisopropylethylamine, 4-methyl-morpholine,1,8-diazabicyclo[5.4.0]undec-7-cene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene and the like or pyridine.

Compounds which carry an acid isostere such as5-oxo-4H-[1,2,4]thiadiazol-3-yl, e.g. as a substituent on R⁶, can beobtained by starting from the corresponding N-hydroxy-benzamidines. TheN-hydroxy-benzamidines can be converted to the desired compounds usingmethods well known to somebody skilled in the art, e.g. intramolecularthiocarbamate formation. The reaction is typically carried out in anaprotic solvent like dimethyl-formamide, dimethyl sulfoxide,acetonitrile, tetrahydrofuran or dichloromethane or mixtures thereof inthe presence of a Lewis acid. A typically used reagent is1,1′-thiocarbonyldiimidazole and a typical acids is boron trifluoride.

Compounds which carry a tertiary hydroxyl, e.g. in a substituent on R⁶,can be obtained by starting from the corresponding ketones. The ketonesare obtained as described in schemes 1-14 by employing an appropriate(alkylcarbonyl)-amino-arene in the amide formation step. The Ketones canbe converted to the desired compounds using methods well known tosomebody skilled in the art, e.g. Grignard addition or addition of otherorganometallic reagents, or reagents capable of generating anucleophilic carbon under the reaction conditions. The reaction istypically carried out in an aprotic solvent like tetrahydrofuran, etheror dichloromethane or mixtures thereof at temperatures between −80° C.and 25° C. under anhydrous conditions.

Compounds of formula (I) which comprise an acid group such as COOH or anacid isostere can form salts with physiologically compatible bases.Examples of such salts are alkaline, earth-alkaline and ammonium saltssuch as e.g. sodium, potassium, calcium and trimethylammonium salt. Onemethod to form such a salt is e.g. by addition of 1/n equivalents of abasic salt such as e.g. M(OH)_(n), wherein M=metal or ammonium cationand n=number of hydroxide anions, to a solution of the compound in asuitable solvent (e.g. ethanol, ethanol-water mixture,tetrahydrofuran-water mixture) and to remove the solvent by evaporationor lyophilisation.

The conversion of compounds of formula (I) into pharmaceuticallyacceptable esters can be carried out e.g. by treatment of a suitablecarboxy group present in the molecule with a suitable alcohol using e.g.a condensating reagent such asbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), N,N-dicylohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) orO-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluoroborate(TPTU). Pharmaceutically acceptable esters can furthermore be preparedby treatment of a suitable hydroxy group present in the molecule with asuitable acid, optionally or if necessary in the presence of acondensating agent as described above.

Insofar as their preparation is not described in the examples, thecompounds of formula (I) as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth above. Starting materials are commercially available, known in theart or can be prepared by methods known in the art or in analogythereto.

As described above, the novel compounds of the present invention havebeen found to inhibit liver carnitine palmitoyl transferase 1 (L-CPT1)activity. The compounds of the present invention can therefore be usedin the treatment and/or prophylaxis of diseases which are modulated byL-CPT1 inhibitors, particularly diseases which are related tohyperglycemia and/or glucose tolerance disorders. Such diseases includee.g. diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment and/or prophylaxis of diseases which aremodulated by L-CPT1 inhibitors, particularly as therapeutically activesubstances for the treatment and/or prophylaxis of hyperglycemia,glucose tolerance disorders, diabetes and associated pathologies, noninsulin dependent diabetes mellitus, obesity, hypertension, insulinresistance syndrome, metabolic syndrome, hyperlipidemia,hypercholesterolemia, fatty liver disease, atherosclerosis, congestiveheart failure and renal failure.

In another preferred embodiment, the invention relates to a method forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by L-CPT1 inhibitors, particularly for the therapeutic and/orprophylactic treatment of hyperglycemia, glucose tolerance disorders,diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The invention also embraces the use of compounds as defined above forthe therapeutic and/or prophylactic treatment of diseases which aremodulated by L-CPT1 inhibitors, particularly for the therapeutic and/orprophylactic treatment of hyperglycemia, glucose tolerance disorders,diabetes and associated pathologies, non insulin dependent diabetesmellitus, obesity, hypertension, insulin resistance syndrome, metabolicsyndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure.

The invention also relates to the use of compounds as described abovefor the preparation of medicaments for the therapeutic and/orprophylactic treatment of diseases which are modulated by L-CPT1inhibitors, particularly for the therapeutic and/or prophylactictreatment of hyperglycemia, glucose tolerance disorders, diabetes andassociated pathologies, non insulin dependent diabetes mellitus,obesity, hypertension, insulin resistance syndrome, metabolic syndrome,hyperlipidemia, hypercholesterolemia, fatty liver disease,atherosclerosis, congestive heart failure and renal failure. Suchmedicaments comprise a compound as described above.

Prevention and/or treatment of hyperglycemia and non insulin dependentdiabetes mellitus is the preferred indication.

The following tests were carried out in order to determine the activityof the compounds of the present invention. Background information on theperformed assays can be found in: Jackson et al., 1999, Biochem. J. 341,483-489 and Jackson et al., 2000, J. Biol. Chem. 275, 19560-19566.

Human liver and muscle CPT1 cDNAs and rat CPT2 cDNA were subcloned inpGAPZB or pGAPZA, respectively. These plasmids were used to transform P.pastoris strain X-33 via electroporation after the preparation ofelectrocompetent cells. High copy number clones were selected wherenecessary using 0.5 or 1 mg/ml Zeocin. Cultures for activitymeasurements were induced for 16 h in YPD medium (1% yeast extract, 2%peptone, 2% glucose). Crude cell extracts were prepared by disruptingthe cells with glass beads or French Press, depending on fermentersizes. After centrifugation, the cell-free extracts were resuspended incell breaking buffer (50 mM Tris, pH7.4, 100 mM KCl, 1 mM EDTA) in thepresence of a protease inhibitor cocktail, before aliquoting andfreezing at −20° C.

CPT activity was measured using a spectrophotometric assay using5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) also called Ellman'sreagent. The HS-CoA released on the formation of acylcarnitine fromcarnitine (500 μM) and palmitoyl-CoA (80 μM) reduced DTNB (300 μM)forming 5-mercapto-(2-nitrobenzoic acid) which absorbed at 410 nm with amolar extinction coefficient of 13600 M⁻¹.cm⁻¹. The assay buffercontained 120 mM KCl, 25 mM Tris, pH 7.4, 1 mM EDTA. This assay was usedfor the identification of selective inhibitors of the liver CPT1 isoformversus the muscle CPT1 and CPT2 isoforms.

The compounds according to formula (I) preferably have an IC50 valuebelow 10 μM, preferably 10 nM to 10 μM, more preferably 10 nM to 5 μM.The following table shows data for some examples.

L-CPT1 inhibition Example IC₅₀ [μmol/l] 2 0.078 32 0.140 73 0.056 920.023 113 0.016

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragees, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 2000 mg,especially about 1 to 500 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-200 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 14-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid was prepared as illustrated in scheme 1.

Step 1. A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (5.0g, 25.4 mmol) in ethanol (120 mL) was treated with 5% palladium onactive carbon (0.24 g, 2.3 mmol, 0.1 equiv.) and the flask was evacuatedand placed under an hydrogen atmosphere. The mixture was stirredvigorously for 2 h and 45′, the palladium was filtered off, washingextensively with ethanol. The solvent was removed in vacuo to yield3-amino-4-hydroxy-benzoic acid methyl ester as a white solid, 4.2 g(100%), MS (ISP): m/e=168.3 (M+H^(+.)). This was used crude in thefollowing reaction.

Step 2. A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K₂CO₃ (14.2g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4equiv.). The mixture was stirred at 70° C. overnight, then filtered toremove the solids. The filtrate was removed under vacuo, and the residuewas purified by flash chromatography (heptane/ethyl acetate gradient) toyield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester,3.65 g (73%) as a light yellow solid, MS (ISP): m/e=235.1(M+CH₃C^(N+.)); δ_(H) (300 MHz; CDCl₃) 7.36 (1H, dd, J=8.5, 2.0), 7.30(1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43(2H, m).

Step 3. To a solution of 5-chloro-2-methoxy-benzenesulfonyl chloride(4.7 g, 19.7 mmol, 1.05 equiv.) in dichloromethane (60 mL) and pyridine(25 mL) was added a solution of3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.6 g,18.8 mmol, 1 equiv.) in dichloro-methane (60 mL). The mixture wasstirred at room temperature overnight then the solvent was removed. Theresidue was purified by flash chromatography to yield4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester as a pink solid, 7.12 g (95%), MS (ISP): m/e=398.0(M+H^(+.)); δ_(H) (300 MHz; CDCl₃) 8.24 (1H, s), 8.07 (1H, s), 7.72 (1H,dd), 7.48 (1H, dd), 6.91 (1H, d), 6.89 (1H, d), 4.10 (2H, m), 3.91 (2H,m), 3.88 (3H, s), 3.63 (3H, s).

Step 4. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (7.1 g, 17.8 mmol) in tetrahydrofuran (100 mL) andmethanol (50 mL) was treated with 3N NaOH (25 mL, 75 mmol, 4.2 equiv.).The mixture was stirred at 45° C. for 1.5 hours. The organic solventswere then removed and the residue acidified with HCl 3N (25 mL). Thewhite precipitate which formed was filtered, washing with water, anddried under high vacuum.4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid was obtained as a white solid, 6.79 g (99%), MS (ISP): m/e=382.0(M−H), which was used crude in the following reaction.

Step 5. A suspension of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (1.0 g, 2.6 mmol) in acetone (130 mL) and tetrahydrofuran (30 mL)was treated with triethylamine (0.5 g, 0.68 mL, 1.9 equiv.) and stirredat room temperature overnight. A solution of cianuric chloride (596 mg,3.2 mmol, 1.24 equiv.) in acetone (20 mL) was added dropwise over aperiod of 1 hour. The reaction mixture was stirred at room temperaturefor 4 hours, 4-amino-benzoic acid ethyl ester (775 mg, 4.7 mmol, 1.8equiv.) was then added. The reaction mixture was stirred at roomtemperature overnight, the solvents were then removed. The residue waspurified by flash chromatography, to yield4-{[4-(5-chloro-2-methoxy-benzene-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester as a white solid, 0.91 g (66%). OH (300 MHz; CDCl₃)8.10 (1H, d), 8.03-8.07 (3H, m), 7.92 (1H, bs), 7.73 (2H, d), 7.70 (1H,d), 7.67 (1H, d), 7.53(1H, d), 7.50 (1H, d), 4.37 (2H, q), 4.03 (2H, m),3.88 (2H, m), 3.56 (3H, s), 1.40 (3H, t).

Step 6. A solution of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester (0.91 g, 1.72 mmol) in tetrahydrofuran (10 mL) andmethanol (10 mL) was treated with 3N NaOH (5 mL, 15 mmol, 8.7 equiv.).The mixture was stirred at 45° C. for 30′. The mixture was thenacidified with HCl 3N (5 mL) and the solid which precipitated wasfiltered, washing with water, and dried under high vacuum.4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid was obtained as a white solid, 0.85 g (98%). MS (ISP): m/e=501.0(M−H); δ_(H) (300 MHz; d6-DMSO) 12.65 (1H, s), 10.35 (1H, s), 8.05 (1H,d), 7.81-7.88 (5H, m), 7.66-7.71 (2H, m), 7.19 (1H, d), 6.98 (1H, d),3.96 (2H, m), 3.85 (2H, m), 3.53 (3H, s).

Example 24-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=519.0 (M−H), was prepared as described in example 1,steps 1 to 6. Step 5 was performed using 4-amino-2-fluoro-benzoic acidethyl ester and yielded4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 6.

Example 32-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=534.9, 536.9 (M−H), was prepared as described inexample 1, steps 1 to 6. Step 5 was performed using4-amino-2-chloro-benzoic acid methyl ester and yielded2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carbonyl]-amino}-benzoicacid methyl ester, which was hydrolyzed in step 6.

Example 45-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylicacid

5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylicacid, MS (ISP): m/e=502.0, 503.9 (M−H), was prepared as described inexample 1, steps 1 to 6. Step 5 was performed using5-amino-pyridine-2-carboxylic acid ethyl ester and yielded5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylicacid ethyl ester, which was hydrolyzed in step 6.

Example 54-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoicacid, MS (ISP): m/e=531.0 (M−H), was prepared as described in example 1,steps 1 to 6. Step 5 was performed using 4-amino-2-methoxy-benzoic acidethyl ester and yielded4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoicacid ethyl ester, which was hydrolyzed in step 6.

Example 64-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoicacid, MS (ISP): m/e=515.0 (M−H), was prepared as described in example 1,steps 1 to 6. Step 5 was performed using 4-amino-2-methyl-benzoic acidethyl ester and yielded4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoicacid ethyl ester, which was hydrolyzed in step 6.

Example 74-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoicacid, MS (ISP): m/e=515.3 (M−H), was prepared as described in example 1,steps 1 to 6. Step 5 was performed using thionyl chloride in toluene anddimethyl-formamide for the formation of the acyl chloride, and4-amino-3-methyl-benzoic acid methyl ester was used for the coupling,yielding4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoicacid methyl ester, which was hydrolyzed in step 6.

Example 82-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylicacid

2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylicacid, MS (ISP): m/e=508.3 (M−H), was prepared as described in example 1,steps 1 to 6. Step 5 was performed using thionyl chloride in toluene anddimethylformamide for the formation of the acyl chloride, and2-amino-thiazole-4-carboxylic acid ethyl ester was used for thecoupling, yielding2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylicacid ethyl ester, which was hydrolyzed in step 6.

Example 94-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide

Step 1. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (example 1, steps 1 to 4) (1.0 g, 2.6 mmol) in dichloromethane (50mL) was treated with N,N-diisopropyl ethyl amine (0.34 g, 2.6 mmol) andcooled to 0° C. Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate(2.4 g, 5.2 mmol) was added, and the mixture was stirred at 0° C. for 1min. 4-Aminobenzonitrile (1.2 g, 10.4 mmol) was added and the mixturewas stirred at room temperature overnight. The solvent was evaporated,and the crude was purified by flash chromatography (heptane/ethylacetate gradient) yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (4-cyano-phenyl)-amide as a white solid, 0.18 g (14%), MS (ISP):m/e=482.0 (M−H).

Step 2. A microwave tube was charged with a solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (4-cyano-phenyl)-amide (50 mg, 0.10 mmol) in dimethylformamide (2.0mL). Ammonium chloride (102 mg, 1.9 mmol) and sodium azide (121 mg, 1.9mmol) were added and the tube was sealed under an argon atmosphere andirradiated in a microwave oven at a temperature of 155° C. for 35 min.The mixture was then acidified with HCl 1N and extracted three timeswith ethyl acetate. The combined organic extracts were dried over sodiumsulfate and evaporated. The crude was resuspended in dichloromethane andsonicated. Filtration yielded4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide as a white solid, 35 mg (64%),MS (ISP): m/e=525.0, 527.0 (M−H).

Example 104-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide

Step 1. A solution of hydroxylamine hydrochloride (90 mg, 1.3 mmol) indimethyl sulfoxide (1.25 mL) was treated with triethylamine (131 mg,0.18 mL, 1.3 mmol) and stirred at room temperature for 5 min. The solidswere filtered off, and4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (4-cyano-phenyl)-amide (125 mg, 0.26 mmol) was added. The mixturewas stirred at 75° C. for 1.5 hours. After cooling back to roomtemperature, the mixture was diluted with water and extracted with ethylacetate. The organic phase was extracted three times with 0.5N HCl. Thecombined acidic aqueous layer was then rebasified with 1N NaOH andextracted three times with ethyl acetate. The organic layer was washedwith water, dried over sodium sulfate and evaporated.4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide was obtained as a whitesolid, 97 mg (73%), MS (ISP): m/e=517.0 (M+H^(+.)).

Step 2. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (97 mg, 0.19 mmol) indimethylformamide (2.0 mL) was treated with pyridine (0.020 mL, 0.20mmol) and the mixture was cooled at 0° C. Chloroformic acid 2-ethylhexylester (36 mg, 0.19 mmol) was added dropwise and the mixture was stirredat 0° C. for 30 min. The mixture was diluted with water and extractedthree times with ethyl acetate. The combined organic extracts were driedover sodium sulfate and evaporated. The residue was suspended in xylene(8.0 mL) and refluxed for 2 hours. Upon cooling to room temperature asolid precipitated, which was filtered and dried under high vacuum.4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide wasobtained as a white solid, 74 mg (73%), MS (ISP): m/e=541.1, 542.7(M−H).

Example 114-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in scheme 12.

Step 1. 4-Amino-3-nitrobenzoic acid (5.0 g, 27.4 mmol) was dissolved inethanol (100 mL) and treated with a 2N solution of HCl in ether (30 mL).The reaction mixture was refluxed for 16 h, then the solvent was removedin vacuo. The crude compound was dissolved in dichloromethane and washedwith NaOH 0.5N. The organic phase was dried over sodium sulfate and thesolvent was removed. 4-Amino-3-nitrobenzoic acid ethyl ester was thusobtained as a yellow solid, 4.6 g, (79%), MS (ISP): m/e=211.1(M+H^(+.)), and used crude in the following reaction.

Step 2. A solution of 4-amino-3-nitrobenzoic acid ethyl ester (4.1 g,19.7 mmol) in acetonitrile (30 mL) was treated with triethylamine (25mL) and dimethylaminopyridine (0.24 g, 2.0 mmol). Di-tert-butyldicarbonate (6.5 g, 29.6 mmol) was added dropwise at room temperatureover a period of 30 minutes. The reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with water anddichloromethane. The organic phase was separated, dried over sodiumsulfate and the volatiles were then evaporated. The residue wasredissolved in dichloromethane (150 mL) and cooled to 0° C.Trifluoroacetic acid (6.0 mL) was added, and the mixture was stirred at0° C. for 2 hours. The mixture was diluted with saturated NaHCO₃ and theorganic phase was separated. The aqueous phase was extracted twice withdichloromethane. The combined organic phases were dried over sodiumsulfate and evaporated. The residue was purified by flash chromatography(dichloromethane/methanol gradient), yielding4-tert-butoxycarbonylamino-3-nitro-benzoic acid ethyl ester as a lightyellow solid, 3.5 g (57%), MS (ISP): m/e=309.4 (M−H).

Step 3. 4-Tert-butoxycarbonylamino-3-nitro-benzoic acid ethyl ester (3.5g, 11.3 mmol) was dissolved in ethanol (300 mL) and 10% palladium oncarbon was added (0.45 g, 0.42 mmol). The mixture was evacuated andfilled with hydrogen, then stirred at room temperature for 1 hour. Thecatalyst was filtered, washing with ethanol, and the solvent wasevaporated. The crude 3-amino-4-tert-butoxycarbonylamino-benzoic acidethyl ester thus obtained [3.1 g, 95%, MS (ISP): m/e=279.3 (M−H)] wasused as such in the following reaction.

Step 4. 3-Amino-4-tert-butoxycarbonylamino-benzoic acid ethyl ester (3.1g, 11.1 mmol) was dissolved in dimethylformamide (50 mL) and treatedwith NaH (˜55% dispersion in oil) (0.3 g, 12.2 mmol). The reactionmixture was stirred at room temperature for 1 hour, dibromoethane (8.3g, 3.8 mL, 44.2 mmol) was then added, and the mixture stirred forfurther 1 hour at room temperature. K₂CO₃ (6.11 g, 44.2 mmol) was addedand the reaction mixture was stirred at 70° C. for 17 hours. A furtheraliquot of NaH (˜55% dispersion in oil) (0.3 g, 12.2 mmol) was addedand, 3 hours later, a further aliquot of dibromoethane (2.1 g, 11.1mmol). Stirring was continued at 70° C. for 18 hours. Water was addedand the mixture was extracted three times with dichloromethane. Thecombined organic phases were dried over sodium sulfate and evaporated.The residue was purified by flash chromatography, yielding3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester6-ethyl ester as a light yellow solid, 1.0 g (29%), MS (ISP): m/e=307.3(M+H^(+.)); δ^(H) (300 MHz; CDCl₃) 7.58 (1H, d), 7.34 (1H, d), 7.25 (1H,s), 4.33 (2H, q), 4.09 (1H, bs), 3.79 (2H, m), 3.43 (2H, m), 1.53 (9H,s), 1.37 (3H, t).

Step 5. 3,4-Dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butylester 6-ethyl ester (300 mg, 0.98 mmol) was dissolved in dichloromethane(20 mL) and pyridine (2 mL). N,N-Diisopropylethylamine (127 mg, 0.98mmol) and 5-chloro-2-methoxy-benzensulfonyl chloride (300 mg, 1.24 mmol)were added, and the mixture was stirred at room temperature overnight.The solvent was evaporated, and the crude compound was purified by flashchromatography, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylicacid 1-tert-butyl ester 6-ethyl ester as a light yellow gum, 435 mg(87%), δ_(H) (300 MHz; CDCl₃) 8.17 (1H, s), 8.05 (1H, s), 7.82 (1H, d),7.74 (1H, d), 7.46 (1H, dd), 6.82 (1H, d), 4.35 (2H, q), 3.93 (2H, m),3.71 (2H, m), 3.56 (3H, s), 1.48 (9H, s), 1.39 (3H, t).

Step 6. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylicacid 1-tert-butyl ester 6-ethyl ester (430 mg, 0.84 mmol) intetrahydrofuran (10 mL) and methanol (10 mL) was treated with 2N NaOH (5mL). The mixture was stirred at room temperature for 1 hour. The organicsolvents were then partially removed and the residue acidified with HCl1N (10 mL). The precipitate which formed was filtered, washing withwater, and dried under high vacuum.4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylicacid 1-tert-butyl ester was obtained as a light yellow gum, 386 mg(95%), MS (ISP): m/e=481.1 (M−H), which was used crude in the followingreaction.

Step 7. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylicacid 1-tert-butyl ester (100 mg, 0.21 mmol) in acetone (30 mL) andtetrahydrofuran (10 mL) was treated with triethylamine (21 mg, 0.21mmol) and stirred at room temperature 1 hour. A solution of cianuricchloride (46 mg, 0.25 mmol) in tetrahydrofurane (2 mL) was addeddropwise over a period of 1 hour. The reaction mixture was stirred atroom temperature for 2 hours, then 4-amino-benzoic acid ethyl ester (51mg, 0.31 mmol) and a further aliquot of triethylamine (42 mg, 0.42 mmol)were added. The reaction mixture was stirred at room temperature for 48hours, the solvents were then removed. The residue was purified by flashchromatography, to yield4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylicacid tert-butyl ester as a light yellow solid, 100 mg (77%), δ_(H) (300MHz; CDCl₃) 8.01-8.08 (4H, m), 7.94 (1H, d), 7.73-7.77 (3H, m), 7.48(1H, dd), 6.82 (1H, d), 4.38 (2H, q), 3.89 (2H, m), 3.64 (2H, m), 3.47(3H, s), 1.48 (9H, s), 1.40 (3H, t).

Step 8. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylicacid tert-butyl ester (95 mg, 0.15 mmol) in trifluoroacetic acid (2 mL)was stirred at room temperature 2 hours. The volatiles were removed andthe residue was purified by trituration in dichloromethane.4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid ethyl ester was obtained as a white solid, 61 mg (76%), MS (ISP):m/e=530.3, 532.3 (M+H^(+.)).

Step 9. A suspension of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid ethyl ester (30 mg, 0.06 mmol) in tetrahydrofuran (2 mL) andmethanol (2 mL) was treated with NaOH 2N (2 mL) and warmed until a clearsolution was obtained. The mixture was stirred at room temperature 2hours, the organic solvents were then partially removed. The aqueousslurry was acidified with HCl 1N (4 mL) and the resulting precipitatefiltered, washing with water.4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid was obtained as a white solid, 26 mg (91%), MS (ISP): m/e=499.9,501.9 (M−H); δ_(H) (300 MHz; d6-DMSO) 12.67 (1H, s), 10.15 (1H, s), 7.91(4H, s), 7.89 (1H, s), 7.81 (1H, s), 7.73 (1H, d), 7.63 (1H, d), 7.23(1H, d), 6.88 (1H, bs), 6.66 (1H, d), 3.64 (2H, bs), 3.53 (3H, s), 2.99(2H, bs).

Example 125-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-pyridine-2-carboxylicacid

5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-pyridine-2-carboxylicacid, MS (ISP): m/e=503.3 (M+H^(+.)), was prepared as described inexample 11, steps 1 to 9. Step 7 was performed using5-amino-pyridine-2-carboxylic acid ethyl ester and yielded4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(6-ethoxycarbonyl-pyridin-3-ylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylicacid tert-butyl ester. This was deprotected in step 8 to5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-pyridine-2-carboxylicacid ethyl ester, which was hydrolyzed to the title compound in step 9.

Example 134-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=518.0 (M−H), was prepared as described in example11, steps 1 to 9. Step 7 was performed using 4-amino-2-fluoro-benzoicacid ethyl ester and yielded4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylicacid tert-butyl ester. This was deprotected in step 8 to4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed to the title compound in step 9.

Example 144-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 2 and 3.

Step 1. A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (30 g,152 mmol) in acetone (1000 mL) was charged into a 2 L reactor andtreated with K₂CO₃ (31.5 g, 228 mol) and benzyl bromide (52 g, 36.1 mL,304 mmol). The mixture was mechanically stirred at heated at reflux for16 hours under a light argon flux. After cooling to room temperature thesolvent was evaporated. The residue was taken up in ethyl acetate/waterand the two phases were separated. The aqueous phase was extracted threetimes with ethyl acetate (total solvent volume: 1.5 L, total watervolume 1 L). The combined organic phases were dried over sodium sulfateand evaporated. 4-Benzyloxy-3-nitro-benzoic acid methyl ester thusobtained was used crude in the following reaction.

Step 2. A solution the crude 4-benzyloxy-3-nitro-benzoic acid methylester from the previous step in tetrahydrofurane (150 mL) and MeOH (600mL) was treated with KOH 3N (152 mL) and stirred at room temperature for18 hours. The mixture was acidified with HCl 3N. The precipitate thusformed was filtered, washing with MeOH/water 1:1 and dried under vacuum.4-Benzyloxy-3-nitro-benzoic acid (42 g, 95% over two steps) was obtainedas a white solid, which was used crude in the following reaction.

Step 3. A suspension of 4-benzyloxy-3-nitro-benzoic acid (36 g, 132mmol) in toluene (1000 mL) and dimethylformamide (3 mL) was treated withthionyl chloride (47 g, 28.7 mL, 395 mmol) and stirred at 90° C. for 18hours. The volatiles were evaporated completely and the residue driedunder high vacuum. 4-Benzyloxy-3-nitro-benzoyl chloride thus obtained(37.5 g, 97%) was used crude in the following reaction.

Step 4. A solution of 4-amino-benzoic acid ethyl ester (17 g, 103 mmol)in dichloromethane (500 mL) and triethylamine (20.8 g, 28.5 mL, 206mmol) was treated with dimethylaminopyridine (0.63 g, 5 mmol) and4-benzyloxy-3-nitro-benzoyl chloride (30 g, 103 mmol). The mixture wasstirred at room temperature overnight, while a thick white precipitateformed. The slurry was diluted with water (10 mL) and stirredvigorously, then filtered, washing with dichloromethane and water. Thesolid was dried under high vacuum to yield4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester as a whitesolid, 26.5 g (61%), MS (ISP): m/e=419.3 (M−H).

Steps 5 and 6. A solution of4-(4-benzyloxy-3-nitro-benzoylamino)-benzoic acid ethyl ester (26 g, 63mmol) in DMF (2644 mL) was treated with 10% palladium on carbon (5.3 g).The reaction vessel was evacuated and filled with hydrogen. The mixturewas stirred at room temperature for 4 hours, then the catalyst wasfiltered, washing with a small quantity of dimethylformamide. Theresulting solution, containing crude4-(3-amino-4-hydroxy-benzoylamino)-benzoic acid ethyl ester, wasconcentrated to a volume of 300 mL, and treated with K₂CO₃ (34.1 g, 247mmol) and 1,2-dibromoethane (46.4 g, 247 mmol). The resulting mixturewas warmed at 70° C. and stirred for 18 hours. The mixture was thenconcentrated to a volume of 100 mL and diluted with ethyl acetate andwater. The organic phase was separated, washed three times with water,dried over sodium sulfate and evaporated. The residue was taken up inmethanol and sonicated. The white solid was filtered, yielding pure4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acidethyl ester (8.6 g). The filtrate was evaporated and the residuepurified by flash chromatography (toluene/acetonitrile gradient)providing further 2 g of material.4-[(3,4-Dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acidethyl ester was thus obtained as a white solid, 10.6 g (52%), MS (ISP):m/e=327.0 (M+H^(+.)); δ_(H) (300 MHz; d6-DMSO) 10.27 (1H, s), 7.92 (4H,s), 7.16-7.19 (2H, m), 6.75 (1H, d), 6.04 (1H, s), 4.29 (2H, q), 4.19(2H, s), 3.32 (2H, s), 1.32 (3H, t).

Step 7 and 8. A solution of4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acidethyl ester (27 mg, 0.085 mmol) in pyridine (0.4 mL) was treated with asolution of 3-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) inpyridine (0.2 mL). The resulting mixture was stirred at room temperaturefor 18 hours. The pyridine was evaporated, and the residual crude4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester was dissolved in ethanol (0.6 mL) and treated with KOH3N (0.15 mL). The resulting mixture was stirred at room temperatureovernight. The mixture was acidified with HCl 3N and evaporated. Theresidue was purified by preparative HPLC (ZORBAX Eclipse XDB-C18,21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid).4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid (17.1 mg, 44%) was obtained as an off-white solid, MS (ISP):m/e=455.0 (M−H).

Example 154-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=472.9 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using2,5-difluoro-benzenesulfonyl chloride and yielded4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 164-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=468.9 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using5-fluoro-2-methyl-benzenesulfonyl chloride and yielded4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 174-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=502.9 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using3-difluoromethoxy-benzenesulfonyl chloride and yielded4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 184-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=466.5 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using3,5-dimethyl-benzenesulfonyl chloride and yielded4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 194-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=505.1 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using3-trifluoromethyl-benzenesulfonyl chloride and yielded4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 204-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=471.1 (M−H), was prepared as described for example14, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonylchloride and yielded4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 212-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

2-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=523.0 (M−H), was prepared as described for example14, steps 1 to 8. Step 4 was performed using 4-amino-2-fluoro-benzoicacid ethyl ester, yielding4-(4-benzyloxy-3-nitro-benzoylamino)-2-fluoro-benzoic acid ethyl ester,which was reduced to 4-(3-amino-4-hydroxy-benzoylamino)-2-fluoro-benzoicacid methyl ester in step 5 and cyclized to4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-2-fluoro-benzoicacid ethyl ester in step 6. Step 7 was performed using3-trifluoromethyl-benzenesulfonyl chloride and yielded2-fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 224-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=489.1 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using 3-chloro-benzenesulfonylchloride and yielded4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 232-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

2-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=473.1 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using 3-fluoro-benzenesulfonylchloride and yielded2-fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 244-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=491.1 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using2,5-difluoro-benzenesulfonyl chloride and yielded4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 252-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

2-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid, MS (ISP): m/e=487.1 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using5-fluoro-2-methyl-benzenesulfonyl chloride and yielded2-fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 264-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=521.2 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using3-difluoromethoxy-benzenesulfonyl chloride and yielded4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]α-azine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 274-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=483.3 (M−H), was prepared as described for example21, steps 1 to 8. Step 7 was performed using3,5-dimethyl-benzenesulfonyl chloride and yielded4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 8.

Example 284-{[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

4-[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid, MS (ISP): m/e=500.0 (M+H^(+.)), was prepared as described forexample 21, steps 1 to 8. Step 7 was performed using3-cyano-benzenesulfonyl chloride and yielded4-{[4-(3-cyano-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 8 at both the carboxylicacid ester and the cyano position.

Example 296-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinicacid

6-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinicacid, MS (ISP): m/e=502.1 (M−H), was prepared as described for example14, steps 1 to 8. Step 4 was performed using 6-amino-nicotinic acidmethyl ester, yielding 6-(4-benzyloxy-3-nitro-benzoylamino)-nicotinicacid methyl ester, which was reduced to6-(3-amino-4-hydroxy-benzoylamino)-nicotinic acid methyl ester in step 5and cyclized to6-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-nicotinic acidmethyl ester in step 6. Step 7 was performed using5-chloro-2-methoxy-benzenesulfonyl chloride and yielded6-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinicacid methyl ester, which was hydrolyzed in step 8.

Example 302-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. 5-Chloro-2-methoxybenzenesulfonyl chloride (5.77 g, 2.39 mmol)was added to a solution of 3-amino-4-hydroxy-benzoic acid methyl ester(example 1, step 1; 4.00 g, 23.9 mmol) in pyridine (38 mL). Thehomogeneous solution was stirred at room temperature for 72 h, thenpartitioned between ethyl acetate and 2 M aq. hydrochloric acidsolution. The organic layer was washed with brine, dried (MgSO₄), andevaporated. The residue was triturated in ethyl acetate to furnish3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (7.19 g, 81%). Pink solid, MS (ISP)=370.0 (M−H)⁻.

Step 2. Potassium carbonate (3.87 g, 28.0 mmol) was added to a solutionof 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (2.08 g, 5.59 mmol) and dibromomethane (2.92 g, 16.5 mmol)in N,N-dimethylformamide (35 mL), and the suspension was heated at 80°C. for 48 h, then the reaction mixture was partitioned between water anddichloromethane. The organic layer was washed with brine, dried (MgSO₄),and evaporated. Chromatography (SiO₂, heptane-ethyl acetate gradient)produced3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester (2.13 g, 99%). White solid, MS (ISP)=384.1 (M+H)⁺.

Step 3. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid. Light red solid, MS (ISP)=368.1 (M−H)⁻.

Step 4. A solution of3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10mL) was stirred at room temperature for 15 min, then4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and thesolution was stirred at 60° C. for 18 h. After cooling, the reactionmixture was partitioned between water, heptane, and ethyl acetate. Theorganic layer was washed with brine, dried (MgSO₄), and evaporated.Chromatography (SiO₂, heptane-ethyl acetate gradient) produced2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)⁺.

Step 5. Hydrolysis of2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester, in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=521.1 (M−H)⁻.

Example 314-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=487.1 (M−H)⁻, was produced as described inexample 30, steps 1 to 5. Step 4 was performed using 4-aminobenzoic acidethyl ester and yielded4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 5.

Example 324-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid

The title compound, MS (ISP)=507.2 (M+H)⁺, was produced as described inexample 30, steps 1 to 5. Step 4 was performed using4-amino-2-fluoro-benzoic acid ethyl ester and yielded4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 5.

Example 333-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid phenylamide

The title compound, MS (ISP)=445.2 (M+H)⁺, was produced as described inexample 30, steps 1 to 4. Step 4 was performed using aniline as aminereagent.

Example 343-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid pyridin-3-ylamide

The title compound, MS (ISP)=446.1 (M+H)⁺, was produced as described inexample 30, steps 1 to 4. Step 4 was performed using 3-aminopyridine asamine reagent.

Example 354-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. A mixture of3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (example 30, step 1; 200 mg, 0.537 mmol), benzaldehydedimethyl acetal (0.5 mL) and toluene-4 sulfonic acid monohydrate (10 mg,54 μmol) was stirred at 100° C. for 48 h. After cooling, heptane wasadded, and the precipitate was collected by filtration to afford3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester (208 mg, 84%). Light yellow solid, MS (ISP)=460.2(M+H)⁺.

Step 2. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=443.9 (M−H)⁻.

Step 3. Reaction of3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylicacid with 4-aminobenzoic acid ethyl ester in accordance with the generalmethod of example 30, step 4 produced4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. Off-white solid, MS (ISP)=593.2 (M+H)⁺.

Step 4. Hydrolysis of4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester, in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=563.2 (M−H)⁻.

Example 364-{[9-(5-Chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 4.

Step 1. Potassium carbonate (818 mg, 5.92 mmol) was added to a solutionof 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (example 30, step 1; 1.00 g, 2.69 mmol) and1,3-dibromopropane (597 mg, 2.96 mmol) in N,N-dimethylformamide (17 mL),and the suspension was heated at 60° C. for 5 h, then the reactionmixture was partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried (MgSO₄), and evaporated.Chromatography (SiO₂, heptane-ethyl acetate gradient) produced9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylicacid methyl ester (996 mg, 90%). White solid, MS (ISP)=412.1 (M+H)⁺.

Step 2. Hydrolysis of9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylicacid. White solid, MS (ISP)=396.1 (M−H)⁻.

Step 3. Reaction of9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carboxylicacid with 4-aminobenzoic acid ethyl ester in accordance with the generalmethod of example 30, step 4 produced4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid ethyl ester. White solid, MS (ISP)=545.3 (M+H)⁺.

Step 4. Hydrolysis of4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid ethyl ester in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=515.2 (M−H)⁻.

Example 372-Chloro-4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=548.9 (M−H)⁻, was produced as described inexample 36, steps 1 to 4. Step 3 was performed using ethyl4-amino-2-chlorobenzoate and yielded2-chloro-4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 384-{[6-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=529.0 (M−H)⁻, was produced in analogy withexample 36, steps 1 to 4. Step 1 was performed using 1,4-dibromobutane,yielding6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 392-Chloro-4-{[6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=565.2 (M+H)⁺, was produced as described inexample 38, steps 1 to 4. Step 3 was performed using ethyl4-amino-2-chloro-benzoate and yielded2-chloro-4-{[6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 404-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. 4-Hydroxy-3-nitro-5-trifluoromethyl-benzoic acid methyl esterwas hydrogenated in analogy with example 1, step 1 to produce3-amino-4-hydroxy-5-trifluoromethyl-benzoic acid methyl ester. Yellowsolid, MS (ISP)=234.1 (M−H)⁻.

Step 2. A suspension of 3-amino-4-hydroxy-5-trifluoromethyl-benzoic acidmethyl ester (4.66 g, 19.8 mmol) and 5-chloro-2-methoxybenzenesulfonylchloride (4.78 g, 19.8 mmol) in toluene (38 mL) was heated at reflux for48 h. After cooling, the precipitate was collected by filtration andwashed with toluene to afford3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoicacid methyl ester. Off-white solid, MS (ISP)=438.0 (M−H)⁻.

Step 3. Cyclization of3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoicacid methyl ester with dibromomethane in accordance with example 30,step 2 furnished3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester. White foam, MS (ISP)=451.9 (M+H)⁺.

Step 4. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in analogy with example 1, step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=436.0 (M−H)⁻.

Step 5. Reaction of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylicacid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. Light yellow solid, MS (ISP)=584.9 (M+H)⁺.

Step 6. Hydrolysis of4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester in analogy with example 1, step 6 afforded the titlecompound. White solid, MS (ISP)=554.9 (M−H)⁻.

Preparation of the Starting Material:

A solution of 3-trifluoromethyl-4-hydroxybenzoic acid (5.00 g, 24.3mmol) in 15% methanolic sulfuric acid solution (50 mL) was heated atreflux over 48 h, then poured upon ice and extracted with ethyl acetate.The organic layer was washed with 1 M aq. sodium carbonate solution andbrine, dried (MgSO₄), and evaporated to afford4-hydroxy-3-trifluoromethyl-benzoic acid methyl ester (4.67 g, 87%).Off-white solid, MS (ISP)=219.0 (M−H)⁻.

65% aq. nitric acid solution (1.76 mL, 39 mmol) and fuming nitric acid(3.25 mL, 78 mmol) were added at −10° C. to a solution of4-hydroxy-3-trifluoromethyl-benzoic acid methyl ester (4.31 g, 19.6mmol) in acetic acid (54 mL). The ice bath was removed and the solutionwas stirred at room temperature for 5 h, then partitioned between waterand ethyl acetate. The organic layer was washed with brine, dried(MgSO₄), and evaporated to afford4-hydroxy-3-nitro-5-trifluoromethyl-benzoic acid methyl ester (5.16 g,99%). Orange solid, MS (ISP)=263.9 (M−H)⁻.

Example 414-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=569.0 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-trifluoromethyl-benzoicacid methyl ester (example 40, step 2) and 1,2-dibromoethane, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 424-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. 3-Methoxy-4-hydroxy-5-nitro-benzoic acid methyl ester (J. Am.Chem. Soc. 1983, 105, 5015) was hydrogenated in analogy with example 1,step 1 to produce 3-amino-4-hydroxy-5-methoxy-benzoic acid methyl ester.Dark green solid, MS (ISP)=198.3 (M+H)⁺.

Step 2. 3-Amino-4-hydroxy-5-methoxy-benzoic acid methyl ester wasreacted with 5-chloro-2-methoxybenzenesulfonyl chloride in accordancewith the general method of example 40, step 2 and led to3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoicacid methyl ester. Light grey solid, MS (ISP)=400.1 (M−H)⁻.

Step 3. Cyclization of3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoicacid methyl ester with dibromomethane in accordance with example 30,step 2 furnished3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester. White solid, MS (ISP)=414.2 (M+H)⁺.

Step 4. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in analogy with example 1, step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=398.0 (M−H)⁻.

Step 5. Reaction of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carboxylicacid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. White solid, MS (ISP)=547.2 (M+H)⁺.

Step 6. Hydrolysis of4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester in analogy with example 1, step 6 afforded the titlecompound. White solid, MS (ISP)=517.1 (M−H)⁻.

Example 434-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=531.1 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoicacid methyl ester (example 42, step 2) and 1,2-dibromoethane, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford4-(5-chloro-2-methoxy-benzene-sulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 444-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. 3-Fluoro-4-hydroxy-5-nitro-benzoic acid methyl ester washydrogenated in analogy with example 1, step 1 to produce3-amino-5-fluoro-4-hydroxy-benzoic acid methyl ester. Light yellowsolid, MS (ISP)=184.1 (M−H)⁻.

Step 2. 3-Amino-5-fluoro-4-hydroxy-benzoic acid methyl ester was reactedwith 5-chloro-2-methoxybenzenesulfonyl chloride in accordance with thegeneral method of example 40, step 2 and led to3-(5-chloro-2-methoxy-benzenesulfonylamino)-5-fluoro-4-hydroxy-benzoicacid methyl ester. White solid, MS (ISP)=388.2 (M−H)⁻.

Step 3. Cyclization of3-(5-chloro-2-methoxy-benzenesulfonylamino)-5-fluoro-4-hydroxy-benzoicacid methyl ester with dibromomethane in accordance with example 30,step 2 furnished3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester. White solid, MS (ISP)=402.0 (M+H)⁺.

Step 4. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in analogy with example 1, step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=386.0 (M−H)⁻.

Step 5. Reaction of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carboxylicacid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. White solid, MS (ISP)=535.2 (M+H)⁺.

Step 6. Hydrolysis of4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester in analogy with example 1, step 6 afforded the titlecompound. White solid, MS (ISP)=505.1 (M−H)⁻.

Preparation of the Starting Material:

A solution of 3-fluoro-4-hydroxybenzoic acid (5.00 g, 32.0 mmol) in 15%methanolic sulfuric acid solution (50 mL) was heated at reflux over 48h, then poured upon ice and extracted with ethyl acetate. The organiclayer was washed with 1 M aq. sodium carbonate solution and brine, dried(MgSO₄), and evaporated to afford 4-fluoro-3-trifluoromethyl-benzoicacid methyl ester (4.48 g, 82%). Off-white solid, MS (ISP)=169.1 (M−H)⁻.

65% aq. nitric acid solution (2.3 mL, 50 mmol) and fuming nitric acid(2.1 mL, 50 mmol) were added at −10° C. to a solution of4-hydroxy-3-trifluoromethyl-benzoic acid methyl ester (4.27 g, 25.1mmol) in diethyl ether (60 mL). The ice bath was removed and thereaction mixture was stirred at room temperature for 16 h, thenpartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried (MgSO₄), and evaporated to afford3-fluoro-4-hydroxy-5-nitro-benzoic acid methyl ester (5.39 g, 100%).Yellow solid, MS (ISP)=214.1 (M−H)⁻.

Example 452-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=539.1 (M−H)⁻, was produced as described inexample 44, steps 1-5. Step 4 was performed using ethyl4-amino-2-chlorobenzoate and yielded2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 5.

Example 464-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid

The title compound, MS (ISP)=523.2 (M−H)⁻, was produced as described inexample 44, steps 1-5. Step 4 was performed using ethyl4-amino-2-fluorobenzoate and yielded4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 5.

Example 474-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=519.1 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-(5-chloro-2-methoxy-benzenesulfonylamino)-5-fluoro-4-hydroxy-benzoicacid methyl ester (example 44, step 2) and 1,2-dibromoethane, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 482-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=552.9 (M−H)⁻, was produced as described inexample 47, steps 1-4. Step 3 was performed using ethyl4-amino-2-chlorobenzoate and yielded2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 494-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

The title compound, MS (ISP)=536.8 (M−H)⁻, was produced as described inexample 47, steps 1-4. Step 3 was performed using ethyl4-amino-2-fluorobenzoate and yielded4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 504-{[7-Chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. A solution of 3-chloro-4-hydroxy-5-nitro-benzoic acid methylester (500 mg, 2.16 mmol) in methanol (22 mL) was added within 10 min toa mixture of iron powder (410 mg, 7.34 mmol) ammonium chloride (647 mg,12.1 mmol) in water (22 mL). The reaction mixture was heated at refluxover 16 h, then after cooling filtered through a pad of diatomaceousearth. The filtrate was extracted with ethyl acetate, dried (MgSO₄), andevaporated. Chromatography (SiO₂, ethyl acetate/heptane 7:3) afforded3-amino-5-chloro-4-hydroxy-benzoic acid methyl ester (293 mg, 68%).Light yellow solid, MS (ISP)=200.1 (M−H)⁻.

Step 2. 3-Amino-5-chloro-4-hydroxy-benzoic acid methyl ester was reactedwith 5-chloro-2-methoxybenzenesulfonyl chloride in accordance with thegeneral method of example 40, step 2 and led to3-chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoicacid methyl ester. White solid, MS (ISP)=404.2 (M−H)⁻.

Step 3.3-Chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoicacid methyl ester with dibromomethane in accordance with example 30,step 2 furnished7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester. White solid, MS (ISP)=418.0 (M+H)⁺.

Step 4. Hydrolysis of7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in analogy with example 1, step 4 produced7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=402.1 (M−H)⁻.

Step 5. Reaction of7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave4-{[7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. Light yellow solid, MS (ISP)=551.1 (M+H)⁺.

Step 6. Hydrolysis of4-{[7-chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester in analogy with example 1, step 6 afforded the titlecompound. White solid, MS (ISP)=520.9 (M−H)⁻.

Preparation of the Starting Material:

65% aq. nitric acid solution (2.4 mL, 54 mmol) and fuming nitric acid(2.2 mL, 54 mmol) were added at −10° C. to a solution of3-chloro-4-hydroxy-benzoic acid methyl ester (5.00 g, 26.8 mmol) indiethyl ether (65 mL). The ice bath was removed and the reaction mixturewas stirred at room temperature for 16 h, then partitioned between waterand ethyl acetate. The organic layer was washed with brine, dried(MgSO₄), and evaporated to afford 3-chloro-4-hydroxy-5-nitro-benzoicacid methyl ester (6.24 g, 100%). Yellow solid, MS (ISP)=230.3 (M−H)⁻.

Example 514-{[8-Chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=534.8 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-chloro-5-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoicacid methyl ester (example 50, step 2) and 1,2-dibromoethane, yielding8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[8-chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 524-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 1 and 6.

Step 1. 4-hydroxy-3-methyl-5-nitro-benzoic acid was hydrogenated inanalogy with example 1, step 1 to produce3-amino-4-hydroxy-5-methyl-benzoic acid methyl ester. Orange solid, MS(ISP)=180.1 (M−H)⁻.

Step 2. 3-Amino-4-hydroxy-5-methyl-benzoic acid methyl ester was reactedwith 5-chloro-2-methoxybenzenesulfonyl chloride in accordance with thegeneral method of example 40, step 2 and led to3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methyl-benzoicacid methyl ester. Light brown solid, MS (ISP)=384.1 (M−H)⁻.

Step 3. Cyclization of3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methyl-benzoicacid methyl ester with dibromomethane in accordance with example 30,step 2 furnished3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester. Off-white solid, MS (ISP)=398.1 (M+H)⁺.

Step 4. Hydrolysis of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylicacid methyl ester in analogy with example 1, step 4 produced3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylicacid. White solid, MS (ISP)=381.9 (M−H)⁻.

Step 5. Reaction of3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carboxylicacid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester. Orange solid, MS (ISP)=530.9 (M+H)⁺.

Step 6. Hydrolysis of4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid ethyl ester in analogy with example 1, step 6 afforded the titlecompound. Brown solid, MS (ISP)=501.1 (M−H)⁻.

Preparation of the Starting Material:

A solution of 4-hydroxy-3-methylbenzoic acid (5.00 g, 32.8 mmol) in 15%methanolic sulfuric acid solution (50 mL) was heated at reflux over 48h, then poured upon ice and extracted with ethyl acetate. The organiclayer was washed with 1 M aq. sodium carbonate solution and brine, dried(MgSO₄), and evaporated to afford 4-hydroxy-3-methyl-benzoic acid methylester (5.18 g, 95%). Brown solid, MS (ISP)=165.1 (M−H)⁻.

65% aq. nitric acid solution (2.7 mL, 60 mmol) and fuming nitric acid(2.5 mL, 60 mmol) were added at −10° C. to a solution of4-hydroxy-3-methyl-benzoic acid methyl ester (4.97 g, 29.9 mmol) indiethyl ether (60 mL). The ice bath was removed and the reaction mixturewas stirred at room temperature for 16 h, then partitioned between waterand ethyl acetate. The organic layer was washed with brine, dried(MgSO₄), and evaporated to afford 4-hydroxy-3-methyl-5-nitro-benzoicacid (6.27 g, 99%). Yellow solid, MS (ISP)=210.1 (M−H)⁻.

Example 534-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=514.9 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methyl-benzoicacid methyl ester (example 52, step 2) and 1,2-dibromoethane, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 4.

Example 543-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid (4-fluoro-phenyl)-amide

The title compound, MS (ISP)=463.1 (M+H)⁺, was produced as described inexample 30, steps 1-4. Step 4 was performed using 4-fluoroaniline asamine reagent.

Example 554-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 7 and 8.

Step 1. Borane-tetrahydrofuran complex solution (1 M in tetrahydrofuran,45 mL, 45 mmol) was added at 0° C. to a suspension ofmethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (2.00 g,8.96 mmol) in tetrahydrofuran (20 mL). The ice bath was removed, thehomogenous solution stirred at room temperature for 2 h, then excessreagent was destroyed by careful addition of methanol (42 mL) at 0° C.After evaporation of volatile material, the residue was taken up in 5%methanolic sulfuric acid solution (25 mL) and the solution was heated atreflux over 80 min. After cooling, the reaction mixture was partitionedbetween ethyl acetate and water, the organic layer was dried (MgSO₄) andevaporated to produce 3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester (1.79 g, 96%). Light yellow solid, MS (ISP)=210.1(M+H)⁺.

Step 2. 3,4-Dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl esterwas reacted with 5-chloro-2-methoxybenzenesulfonyl chloride inaccordance with the general method of example 30, step 1 and led to4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester. Pink solid, MS (ISP)=414.2 (M+H)⁺.

Step 3. Hydrolysis of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid. White solid, MS (ISP)=398.1 (M−H)⁻.

Step 4. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid with ethyl 4-aminobenzoate in accordance with the general method ofexample 30, step 4 produced4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid ethyl ester. White solid, MS (ISP)=547.2 (M+H)⁺.

Step 5. Hydrolysis of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid ethyl ester in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=517.0 (M−H)⁻.

Example 564-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in scheme 7.

Step 1. Sodium hydride (55% dispersion in mineral oil, 603 mg, 13.8mmol) was added to a solution of ethyl glycolate (1.43 g, 13.8 mmol) in1,4-dioxane, and the reaction mixture was heated at 70° C. for 1 h, then5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64g, 6.91 mmol) was added, and stirring was continued at 70° C. for 1 hand at room temperature for 16 h. The reaction mixture was thenneutralized with sat. aq. sodium hydrogencarbonate solution andextracted three times with dichloromethane. The organic layers werepooled, dried (Na₂SO₄), and evaporated. Chromatography (SiO₂,hexane-ethyl acetate gradient) furnished(5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49%).Light yellow liquid, MS (ISP)=305.1 (M+H)⁺.

Step 2. Iron powder (22.8 g, 408 mmol) was added to a solution of(5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (2.28 g, 7.47mmol) in acetic acid (230 mL), and the reaction mixture was heated at60° C. over 150 min, cooled to room temperature, and filtered. Thefiltrate was evaporated, taken up in dichloromethane/methanol 1:1 andneutralized with 1 M aq. sodium carbonate solution. The organic layerwas washed with water and the aqueous layer re-extracted withdichloromethane. The combined organic layers were washed again with 1 Maq. sodium carbonate solution, dried (Na₂SO₄), and evaporated to produce7-bromo-1H-4-oxa-1,5-diaza-naphthalen-2-one (1.46 g, 85%). Off-whitesolid, MS (ISP)=226.9 (M−H)⁻.

Step 3. Borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 32 mL,32 mmol) was added dropwise at 0° C. to a solution of7-bromo-1H-4-oxa-1,5-diaza-naphthalen-2-one (1.45 g, 6.33 mmol) intetrahydrofuran (240 mL). The ice bath was removed and the solutionheated at reflux over 3 h, then volatile material was removed bydistillation. The residue was taken up in 37% aq. hydrochloric acidsolution and the reaction mixture, heated at 100° C. for 75 min,basified to pH 10 with 30% aq. sodium hydroxide solution, and extractedthree times with dichloromethane. The combined organic layers were dried(Na₂SO₄) and evaporated to afford7-bromo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene (944 mg, 69%). Whitesolid, MS (ISP)=215.1 (M+H)⁺.

Step 4. 7-Bromo-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene was reactedwith 5-chloro-2-methoxybenzenesulfonyl chloride in accordance with thegeneral method of example 1, step 3 and led to7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene.White solid, MS (ISP)=420.9 (M+H)⁺.

Step 5. A solution of7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene(200 mg, 0.476 mmol), triethylamine (120 mg, 1.19 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethanecomplex (19 mg, 29 μmol) in ethanol (2 mL) and ethyl acetate (2 mL) washeated at 110° C. under a carbon monoxide atmosphere (70 bar) for 20 h.The reaction mixture was evaporated and the residue chromatographed(SiO₂, toluene-acetonitrile gradient) to produce1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid ethyl ester (132 mg, 67%). Off-white solid, MS (ISP)=413.2 (M+H)⁺.

Step 6. A mixture of1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid ethyl ester (124 mg, 0.30 mmol) in tetrahydrofuran (0.6 mL) and 1 Maq. potassium hydroxide solution (0.60 mL, 0.60 mmol) was stirred at 50°C. over 72 h. Evaporation of volatile material furnished1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid potassium salt (116 mg), which was directly used in the next step.Light yellow solid, MS (ISP)=383.1 (M−K)⁻.

Step 7. Reaction of1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid potassium salt with tert-butyl 4-aminobenzoate in accordance withthe general method of example 30, step 4 produced4-{[1-(5-chloro-2-methoxy-benzene-sulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoicacid tert-butyl ester. White solid, MS (ISP)=560.1 (M+H)⁺.

Step 8.4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoicacid tert-butyl ester (27 mg, 48 μmol) was dissolved in hydrogenchloride solution (4 M in 1,4-dioxane, 1.0 mL) and stirred at roomtemperature for 4 days, then the precipitate was collected by filtrationand washed with ethyl acetate to produce the title compound (21 mg,86%). White solid, MS (ISP)=502.0 (M−H)⁻.

Example 571-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid phenylamide

The title compound, MS (ISP)=460.1 (M+H)⁺, was produced in analogy withexample 30, step 4 from1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid potassium salt (example 56, step 6) and aniline.

Example 584-(5-Chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid phenylamide

The title compound was prepared as illustrated in schemes 1, 4, and 5.

Step 1. Allyl bromide (195 mg, 1.63 mmol) and potassium carbonate (372mg, 2.69 mmol) was added to a solution of3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (example 30, step 1; 200 mg, 0.538 mmol) in acetone, andthe reaction mixture was stirred at 60° C. for 16 h. After cooling,insoluble material was filtered off and the filtrate evaporated toproduce3-[allyl-(5-chloro-2-methoxy-benzenesulfonyl)-amino]-4-allyloxy-benzoicacid methyl ester (243 mg, 100%). Orange solid, MS (ISP)=452.1 (M+H)⁺.

Step 2. A solution of3-[allyl-(5-chloro-2-methoxy-benzenesulfonyl)-amino]-4-allyloxy-benzoicacid methyl ester (243 mg, 0.537 mmol) andcarbonylchlorohydrotris(triphenylphosphine)-ruthenium (15 mg, 16 μmol)in toluene (2.6 mL) was stirred at 95° C. for 16 h, then another portionof carbonylchlorohydrotris(triphenylphosphine)ruthenium (27 mg, 25 μmol)was added, and stirring was continued over 48 h, then the solvent wasevaporated. Chromatography (SiO₂, heptane-ethyl acetate gradient)furnished3-[(5-chloro-2-methoxy-benzenesulfonyl)-propenyl-amino]-4-[(propenyl)oxy]-benzoicacid methyl ester (177 mg, 73%). Light red oil, MS (ISP)=452.1 (M+H)⁺.

Step 3. A solution of3-[(5-chloro-2-methoxy-benzenesulfonyl)-propenyl-amino]-4-[(propenyl)oxy]-benzoicacid methyl ester (170 mg, 0.378 mmol) anddichloro(1,3-dimesityl-4,5-dihydroimidazol-2-ylidene)(phenylmethylene)(tricyclohexylphosphine)ruthenium(32 mg, 38 μmol) in toluene (1.7 mL) was stirred at 45° C. for 24 h,then the solvent was evaporated. Chromatography (SiO₂, heptane-ethylacetate gradient) afforded4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid methyl ester (75 mg, 50%). Light red solid, MS (ISP)=395.7 (M+H)⁺.

Step 4. Hydrolysis of4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid. Light red solid, MS (ISP)=380.1 (M−H)⁻.

Step 5. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid with aniline in accordance with the general method of example 30,step 4 produced the title compound. Orange solid, MS (ISP)=455.2 (M−H)⁻.

Example 59(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=508.1 (M−H)⁻, was produced as described inexample 30, steps 1-5. Step 4 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 60(3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=501.0 (M−H)⁻, was produced as described inexample 30, steps 1-5. Step 4 was performed using ethyl(3-aminophenyl)acetate and yielded(3-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 61(4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=501.1 (M−H)⁻, was produced as described inexample 30, steps 1-5. Step 4 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 62(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=540.1 (M−H)⁻, was produced as described inexample 47, steps 1-4. Step 3 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3)-4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 63(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=533.0 (M−H)⁻, was produced as described inexample 47, steps 1-4. Step 3 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 64(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=526.1 (M−H)⁻, was produced as described inexample 44, steps 1-5. Step 4 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 65(4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=519.1 (M−H)⁻, was produced as described inexample 44, steps 1-5. Step 4 was performed using ethyl(4-aminophenyl)acetate and yielded(2-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 66(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=522.2 (M−H)⁻, was produced in analogy withexample 36, steps 1-4. Step 1 was performed using3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acidmethyl ester (example 30, step 1) and 1,2-dibromoethane, yielding4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 2 to afford4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 3 toproduce(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 67(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=515.2 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 68(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=540.1 (M+H)⁺, was produced as described inexample 55, steps 1-5. Step 4 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 69(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=531.1 (M−H)⁻, was produced as described inexample 55, steps 1-5. Step 4 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 5.

Example 704-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in schemes 7, 8, and 13.

Step 1. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]-thiazine-6-carboxylicacid (example 55, step 3) with tert-butyl 4-aminobenzoate in accordancewith the general method of example 30, step 4 produced4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester. White solid, MS (ISP)=575.2 (M+H)⁺.

Step 2. A suspension of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester (100 mg, 0.174 mmol) in formic acid (2 mL) wastreated with 30% aq. hydrogen peroxide solution (89 μL, 0.87 mmol) andstirred at room temperature, then after 24 h another portion of 30% aq.hydrogen peroxide solution (89 μL, 0.87 mmol) was added. After a totalreaction time of 48 h water (7 mL) was added, then after 30 min theprecipitate was collected by filtration and dried to afford the titlecompound (75 mg, 79%). White solid, MS (ISP)=549.2 (M−H)⁻.

Example 714-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid phenylamide

The title compound, MS (ISP)=459.2 (M+H)⁺, was produced as described inexample 66, steps 1-3. Step 3 was performed using aniline as aminereagent.

Example 723-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=501.3 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using methyl 3-aminobenzoateand yielded3-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid methyl ester, which was hydrolyzed in step 4.

Example 734-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-benzoicacid

The title compound was prepared as illustrated in scheme 10.

Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran,13 mL, 13 mmol) was added over 5 min to a solution of4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature,then after 72 h the reaction mixture was carefully poured upon sat. aq.sodium hydrogencarbonate solution and extracted with ethyl acetate. Theorganic layer was dried (MgSO₄) and evaporated to produce(4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96%). White solid, ¹H-NMR(300 MHz, CDCl₃): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67(d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).

Step 2. A mixture of (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 7.97mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h,then after cooling filtered through a pad of diatomaceous earth. Thefiltrate was evaporated and the residue partitioned between ethylacetate and water, the organic layer was washed with brine, dried(MgSO₄), and evaporated to produce (2-amino-4-bromo-phenyl)-methanol(1.53 g, 90%). Off-white solid, MS (EI)=201.0 (M⁺).

Step 3. A solution of (2-amino-4-bromo-phenyl)-methanol (1.53 g, 7.57mmol) in pyridine (15 mL) was treated with5-chloro-2-methoxybenzenesulfonyl chloride (1.85 g, 7.57 mmol) at roomtemperature and stirred for 72 h, then poured upon ice-cold 2 M aq.hydrochloric acid solution and extracted with ethyl acetate. The organiclayer was washed with brine, dried (MgSO₄), and evaporated to produce agummy residue, from which the product was precipitated by addition oftoluene. The precipitate was collected by filtration and dried to affordN-(5-bromo-2-hydroxy-methyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide(2.51 g, 82%). Off-white solid, MS (ISP)=404.2 (M−H)⁻.

Step 4. A mixture ofN-(5-bromo-2-hydroxymethyl-phenyl)-5-chloro-2-methoxy-benzenesulfonamide(2.51 g, 6.17 mmol), toluene-4-sulfonic acid monohydrate (117 mg, 0.617mmol), and formaldehyde diethyl acetal (15.5 mL) was heated under refluxat 100° C. for 16 h. After cooling, heptane was added to the suspension,which was stirred for 15 min. The precipitate was collected byfiltration and dried to afford7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine(2.25 g, 87%). Off-white solid, MS (ISP)=418.1 (M+H)⁺.

Step 5. A solution of7-bromo-1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine(2.00 g, 4.78 mmol), triethylamine (1.21 g, 11.9 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethanecomplex (200 mg, 0.239 mmol) in methanol (30 mL) and ethyl acetate (30mL) was heated at 130° C. under a carbon monoxide atmosphere (100 bar)for 3 h. The reaction mixture was evaporated and the residuechromatographed (SiO₂, heptane-ethyl acetate gradient) to produce1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylicacid methyl ester (825 mg, 43%). Orange solid, MS (ISP)=398.1 (M+H)⁺.

Step 6. Hydrolysis of1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]-7-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylicacid. Off-white solid, MS (ISP)=382.3 (M−H)⁻.

Step 7. Reaction of1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carboxylicacid with ethyl 4-aminobenzoate in accordance with the general method ofexample 30, step 4 produced4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-benzoicacid ethyl ester. White foam, MS (ISP)=531.1 (M+H)⁺.

Step 8. Hydrolysis of4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-benzoicacid ethyl ester in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=503.1 (M+H)⁺.

Example 74(2-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=524.2 (M+H)⁺, was produced as described inexample 73, steps 1-8. Step 7 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 8.

Example 75(4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=517.1 (M+H)⁺, was produced as described inexample 73, steps 1-8. Step 7 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 8.

Example 762-Chloro-5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=535.0 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using methyl5-amino-2-chlorobenzoate and yielded2-chloro-5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid methyl ester, which was hydrolyzed in step 4.

Example 77(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=590.2 (M−H)⁻, was produced as described inexample 41, steps 1-4. Step 3 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 78(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=583.0 (M−H)⁻, was produced as described inexample 41, steps 1-4. Step 3 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 79(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=536.1 (M−H)⁻, was produced as described inexample 53, steps 1-4. Step 3 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 80(4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=515.1 (M−H)⁻, was produced as described inexample 52, steps 1-6. Step 5 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 81(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=522.1 (M−H)⁻, was produced as described inexample 52, steps 1-6. Step 5 was performed using ethyl2-amino-4-thiazoleacetate and yielded(2-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 82(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=529.0 (M−H)⁻, was produced as described inexample 53, steps 1-4. Step 3 was performed using ethyl(4-aminophenyl)acetate and yielded(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 83(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-5-yl)-aceticacid

The title compound, MS (ISP)=522.1 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using ethyl(2-amino-thiazol-5-yl)-acetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-5-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 842-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-5-carboxylicacid

The title compound, MS (ISP)=508.1 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using2-amino-thiazole-5-carboxylic acid ethyl ester and yielded2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-5-carboxylicacid ethyl ester, which was hydrolyzed in step 4.

Example 85(3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=515.1 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using ethyl(3-aminophenyl)acetate and yielded(3-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 863-(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-propionicacid

The title compound, MS (ISP)=529.0 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using3-(4-amino-phenyl)-propionic acid ethyl ester and yielded3-(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-propionicacid ethyl ester, which was hydrolyzed in step 4.

Example 87(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-5-methyl-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=536.3 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using methyl2-(2-amino-5-methyl-thiazol-4-yl)acetate and yielded(2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-5-methyl-thiazol-4-yl)-aceticacid methyl ester, which was hydrolyzed in step 4.

Example 88(3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyrazol-1-yl)-aceticacid

The title compound, MS (ISP)=505.3 (M−H)⁻, was produced as described inexample 66, steps 1-4. Step 3 was performed using(3-amino-pyrazol-1-yl)-acetic acid ethyl ester and yielded(3-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyrazol-1-yl)-aceticacid ethyl ester, which was hydrolyzed in step 4.

Example 894-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoicacid

Step 1. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carboxylicacid (example 1, step 4) with 2-bromo-5-aminobenzonitrile in accordancewith the general method of example 30, step 4 produced4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid (4-bromo-3-cyano-phenyl)-amide. White solid, MS (ISP)=562.1 (M+H)⁺.

Step 2. A solution of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]oxazine-6-carboxylicacid (4-bromo-3-cyano-phenyl)-amide (109 mg, 0.194 mmol), triethylamine(49 mg, 0.48 mmol), anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethanecomplex (20 mg, 25 μmol) in ethyl acetate (1.5 mL) and 1-propanol (1.5mL) was heated at 110° C. under a carbon monoxide atmosphere for 16 h,then volatile material was removed by distillation. Chromatography ofthe residue (SiO₂; heptane-ethyl acetate gradient, thendichloromethane/methanol 9:1) followed by trituration in dichloromethaneproduced4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoicacid propyl ester (46 mg, 42%). White solid, MS (ISP)=568.2 (M−H)⁻.

Step 3. Hydrolysis of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoicacid propyl ester, in accordance with the general method of example 1,step 6 produced the title compound. White solid, MS (ISP)=526.4 (M−H)⁻.

Example 902-Fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=501.1 (M+H)⁺, was produced as described inexample 1, steps 1-6. Step 3 was performed using2-methoxy-5-methylbenzenesulfonyl chloride, furnishing4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 4, leading to4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 4-amino-2-fluorobenzoate in step 5 andyielded2-fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid ethyl ester, which was hydrolyzed in step 6.

Example 91(2-{[4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=472.1 (M−H)⁻, was produced as described inexample 1, steps 1-6. Step 3 was performed using 3-methylbenzenesulfonylchloride, furnishing4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 4, leading to4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5and yielded(2-{[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 92(2-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=492.0 (M−H)⁻, was produced as described inexample 1, steps 1-6. Step 3 was performed using 3-chlorobenzenesulfonylchloride, furnishing4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 4, leading to4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5and yielded(2-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 93(2-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid

The title compound, MS (ISP)=486.3 (M−H)⁻, was produced as described inexample 1, steps 1-6. Step 3 was performed using3,5-dimethylbenzenesulfonyl chloride, furnishing4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid methyl ester, which was hydrolyzed in step 4, leading to4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5and yielded(2-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 94(3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-pyrazol-1-yl)-aceticacid

The title compound, MS (ISP)=491.1 (M−H)⁻, was produced as described inexample 52, steps 1-6. Step 5 was performed using(3-amino-pyrazol-1-yl)-acetic acid ethyl ester and yielded(3-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-pyrazol-1-yl)-aceticacid ethyl ester, which was hydrolyzed in step 6.

Example 954-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

Step 1. 3,4-Dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester(example 55, step 1) was reacted with 3-chloro-benzenesulfonyl chloridein accordance with the general method of example 30, step 1 and led to4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester. Off-white foam, MS (ISP)=384.1 (M+H)⁺.

Step 2. Hydrolysis of4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid. White solid, MS (ISP)=370.0 (M+H)⁺.

Step 3. Reaction of4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid with tert-butyl 4-aminobenzoate in accordance with the generalmethod of example 30, step 4 produced4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester. White foam, MS (ISP)=545.3 (M+H)⁺.

Step 4. Hydrolysis of4-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester in accordance with the general method of example96, step 2 produced the title compound. White solid, MS (ISP)=487.1(M−H)⁻.

Example 964-{[4-(3-Chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

Step 1. A solution of4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid tert-butyl ester (example 95, step 3; 192 mg, 0.352 mmol) indichloromethane (2 mL) was treated at 0° C. with 3-chloroperbenzoic acid(61 mg, 0.35 mmol). The reaction mixture was stirred at 0° C. for 4 h,then partitioned between dichloromethane and 2 M aq. sodium carbonatesolution. The organic layer was dried (MgSO₄), and evaporated.Chromatography (SiO₂, ethyl acetate) afforded4-{[4-(3-chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester (153 mg, 77%). White solid, MS (ISP)=561.2 (M+H)⁺.

Step 2. A suspension of4-{[4-(3-chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester (153 mg, 0.273 mmol) in formic acid (4 mL) wasstirred for 16 h at room temperature, then the solution obtained wastreated with water, and the suspension was stirred for another 90 min.The precipitate was collected by filtration and dried to produce thetitle compound (126 mg, 92%). White solid, 505.2 (M+H)⁺.

Example 974-{[4-(3-Chloro-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=521.2 (M+H)⁺, was produced in accordancewith the general method of example 70, step 2 from4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid tert-butyl ester (example 95, step 3).

Example 984-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

Step 1. 3,4-Dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester(example 55, step 1) was reacted with 3,5-dimethyl-benzenesulfonylchloride in accordance with the general method of example 30, step 1 andled to4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid methyl ester. White foam, MS (ISP)=378.2 (M+H)⁺.

Step 2. Hydrolysis of4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]thiazine-6-carboxylicacid methyl ester in accordance with the general method of example 1,step 4 produced4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid. White solid, MS (ISP)=364.1 (M+H)⁺.

Step 3. Reaction of4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid with tert-butyl 4-aminobenzoate in accordance with the generalmethod of example 30, step 4 produced4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester. White solid, MS (ISP)=539.3 (M+H)⁺.

Step 4. Hydrolysis of4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester in accordance with the general method of example96, step 2 produced the title compound. White solid, MS (ISP)=483.4(M+H)⁺.

Example 994-{[4-(3,5-Dimethyl-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=499.2 (M+H)⁺, was produced as described inexample 96, steps 1-2. Oxidation of4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid tert-butyl ester (example 98, step 3) in step 1 produced4-{[4-(3,5-dimethyl-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester, which was hydrolyzed in step 2.

Example 1004-{[4-(3,5-Dimethyl-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=515.3 (M+H)⁺, was produced in accordancewith the general method of example 70, step 2 from4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid tert-butyl ester (example 98, step 3).

Example 1014-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=533.3 (M−H)⁻, was produced as described inexample 96, steps 1-2. Oxidation of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylicacid tert-butyl ester (example 70, step 1) in step 1 produced4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino)-benzoicacid tert-butyl ester, which was hydrolyzed in step 2.

Example 102(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid

Step 1. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]thiazine-6-carboxylicacid (example 55, step 3) with tert-butyl (4-aminophenyl)acetate inaccordance with the general method of example 30, step 5 produced(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid tert-butyl ester. Orange solid, MS (ISP)=589.5 (M+H)⁺.

Step 2. Oxidation of(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid tert-butyl ester in accordance with the general method of example96, step 1 produced(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid tert-butyl ester. Off-white solid, MS (ISP)=605.3 (M+H)⁺.

Step 3. Hydrolysis of(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid tert-butyl ester in accordance with the general method of example96, step 2 produced the title compound. White solid, 549.2 (M+H)⁺.

Example 103(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid

The title compound, MS (ISP)=565.2 (M+H)⁺, was produced in accordancewith the general method of example 70, step 2 from(4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid tert-butyl ester (example 102, step 1).

Example 1044-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

Step 1. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]thiazine-6-carboxylicacid (example 55, step 3) with tert-butyl 4-amino-2-fluorobenzoate inaccordance with the general method of example 30, step 5 produced4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid tert-butyl ester. Off-white solid, MS (ISP)=591.2 (M+H)⁺.

Step 2. Hydrolysis of4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid tert-butyl ester in accordance with the general method of example96, step 2 produced the title compound. White solid, MS (ISP)=537.2(M+H)⁺.

Example 1054-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid

The title compound, MS (ISP)=569.1 (M+H)⁺, was produced in accordancewith the general method of example 70, step 2 from4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid tert-butyl ester (example 104, step 1).

Example 1062-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

Step 1. Reaction of4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo-[1,4]thiazine-6-carboxylicacid (example 55, step 3) with tert-butyl 4-amino-2-chloro in step 1 inaccordance with the general method of example 30, step 5 produced2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester. White solid, MS (ISP)=609.1 (M+H)⁺.

Step 2. Hydrolysis of2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester in accordance with the general method of example96, step 2 produced the title compound. White solid, MS (ISP)=553.0(M+H)⁺.

Preparation of tert-butyl 4-amino-2-chlorobenzoate

Lithium tert-butylate (2.2 M in tetrahydrofuran, 6.2 mL, 13.6 mmol) wasadded to a solution of 2-chloro-4-nitrobenzoyl chloride (2.00 g, 9.09mmol) in tetrahydrofuran (12 mL) at 0° C. The orange solution was keptat 0° C. for 1.5 h, then allowed to reach room temperature over 16 h,then partitioned between 1 M aq. sodium carbonate solution and isopropylacetate. The organic layer was dried (MgSO₄) and evaporated to affordtert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 88%) which was directlyused in the next step. Brown oil, MS (EI)=257.1 (M⁺).

To a solution of tert-butyl 2-chloro-4-nitro-benzoate (2.05 g, 7.98mmol) in ethanol 12 mL) and ethyl acetate (108 mL) was added platinum onactivated charcoal (5%, 295 mg), and the mixture was stirred under atroom temperature under a hydrogen atmosphere (1 bar). After filtrationthrough a pad of diatomaceous earth, the filtrate was evaporated toafford tert-butyl 4-amino-2-chlorobenzoate (1.75 g, 96%). Orange solid,MS (EI)=227.2 (M⁺).

Example 1072-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid

The title compound, MS (ISP)=584.9 (M+H)⁺, was produced in accordancewith the general method of example 70, step 2 from2-chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid tert-butyl ester (example 106, step 1).

Example 1084-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester

Step 1. A mixture of 2-amino-4-bromophenol (5.00 g, 26.6 mmol), ethyl2,3-dibromo-propionate (7.84 g, 29.2 mmol), and potassium carbonate(10.3 g, 81.8 mmol) in acetone (55 mL) was heated at reflux for 16 h.After evaporation of volatile material, the residue was partitionedbetween dichloromethane and water. The organic layer was washed with 1 Maq. sodium carbonate solution and brine, dried (MgSO₄), and evaporated.Chromatography (SiO₂, heptane-ethyl acetate gradient produced6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester(5.95 g, 78%). Orange solid, MS (ISP)=286.0 (M+H)⁺.

Step 2. 6-Bromo-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethylester was reacted with 5-chloro-2-methoxy-benzenesulfonyl chloride inaccordance with the general method of example 30, step 1 and led to6-bromo-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester. Yellow solid, MS (ISP)=489.9 (M+H)⁺.

Step 3. A mixture of6-bromo-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester (200 mg, 0.408 mmol), molybdenum hexacarbonyl (108 mg,0.408 mmol), aniline (114 mg, 1.22 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (192 mg, 1.22 mmol)trans-bis(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II)(12 mg, 37 μmol), and tris(tert-butyl)phosphine tetrafluoroborate (6 mg,20 μmol) in tetrahydrofuran (1 mL) was heated for 10 min at 140° C.under microwave irradiation, then the reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried (MgSO₄), and evaporated. Chromatography (SiO₂,heptane-ethyl acetate gradient produced the title compound (111 mg,51%). Off-white foam, MS (ISP)=531.0 (M+H)⁺.

Example 1094-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid

The title compound, MS (ISP)=501.4 (M−H)⁻, was produced in accordancewith the general method of example 1, step 6 from4-(5-chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester.

Example 1104-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester

The title compound, MS (ISP)=549.3 (M+H)⁺, was produced as described inexample 108, steps 1-3. Step 3 was performed using 2-fluoroaniline asamine reagent.

Example 1114-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid

The title compound, MS (ISP)=519.3 (M−H)⁻, was produced in accordancewith the general method of example 1, step 6 from4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester ethyl ester.

Example 1124-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester

The title compound, MS (ISP)=549.3 (M+H)⁺, was produced as described inexample 108, steps 1-3. Step 3 was performed using 3-fluoroaniline asamine reagent.

Example 1134-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid

The title compound, MS (ISP)=519.3 (M−H)⁻, was produced in accordancewith the general method of example 1, step 6 from4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester ethyl ester.

Example 1144-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester

The title compound, MS (ISP)=549.3 (M+H)⁺, was produced as described inexample 108, steps 1-3. Step 3 was performed using 4-fluoroaniline asamine reagent.

Example 1154-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid

The title compound, MS (ISP)=519.1 (0M−H)⁻, was produced in accordancewith the general method of example 1, step 6 from4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester ethyl ester.

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0mg  70.0 mg  Polyvinylpyrrolidone K30 12.5 mg  15.0 mg  Sodium starchglycolate 12.5 mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (KernelWeight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mgIron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcristallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg AceticAcid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of polyethylene glycol400 and water for injection (part). The pH is adjusted to 5.0 by aceticacid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula (I):

wherein: V is N or —C(R⁷)—; W is a single bond or —C(R⁸R⁹)—; X is O, S,SO, SO₂ or N(R¹⁰); Y is —C(R¹¹R¹²)—, —C(R¹¹R¹²)C(R¹³R¹⁴)—,—C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)—, —C(R¹¹R¹²)C(R¹³R¹⁴)C(R¹⁵R¹⁶)C(R¹⁷R¹⁸)— or—C(R¹¹)═C(R¹²)—; R¹, R², R³, R⁴ and R⁵ independently from each other arehydrogen, halogen, cyano, hydroxy, lower-alkyl, fluoro-lower-alkyl,lower-alkoxy, fluoro-lower-alkoxy, lower-alkyl-C(O),lower-alkyl-C(O)—NH, lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂,NH₂—S(O)₂, N(H,lower-alkyl)-S(O)₂ or N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), COOH or lower-alkoxy-C(O),wherein lower-alkyl is optionally substituted with hydroxy, NH₂,N(H,lower-alkyl) or N(lower-alkyl)₂; R⁶ is an aryl or heteroaryl group,which aryl or heteroaryl group is optionally substituted by 1 to 4substituents selected from the group consisting of halogen, hydroxy,cyano, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy,fluoro-lower-alkoxy, lower-alkyl-C(O), lower-alkyl-C(O)—NH,lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O)₂, NH₂—S(O)₂,N(H,lower-alkyl)-S(O)₂, N(lower-alkyl)₂-S(O)₂, NH₂—C(O),N(H,lower-alkyl)-C(O), N(lower-alkyl)₂-C(O), lower-alkoxy-C(O), COOH,1H-tetrazol-5-yl, 5-oxo-4H-[1,2,4]oxadiazol-3-yl,5-oxo-4H-[1,2,4]thiadiazol-3-yl, 5-thioxo-4H-[1,2,4]oxadiazol-3-yl,2-oxo-3H-[1,2,3,5]oxathiadiazol-4-yl, SO₃H, 3-hydroxy-isooxazol-5-yl,6-oxo-6H-pyran-3-yl, 6-oxo-6H-pyran-2-yl, 2-oxo-2H-pyran-3-yl,2-oxo-2H-pyran-4-yl and P(O)(OCH₂CH₃)OH, wherein lower-alkyl isoptionally substituted with COOH, hydroxy, NH₂, N(H,lower-alkyl) orN(lower-alkyl)₂, and wherein fluoro-lower-alkyl is optionallysubstituted with hydroxy; R⁷ is hydrogen, halogen, lower-alkyl,lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, hydroxy orhydroxy-lower-alkyl; R⁸ and R⁹ independently from each other arehydrogen or lower-alkyl; R¹⁰ is hydrogen, lower-alkyl, cycloalkyl,lower-alkyl-C(O), lower-alkyl-S(O)₂, lower-alkoxy-C(O),(lower-alkyl)NH—C(O), or (lower-alkyl)₂N—C(O); R¹¹, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷ and R¹⁸ independently from each other are hydrogen, halogen,hydroxy, lower alkyl, lower-alkoxy, fluoro-lower-alkyl,fluoro-lower-alkoxy, hydroxy-lower-alkyl, aryl, COOH, C(O)O-lower-alkylor cyano; and pharmaceutically acceptable salts and esters thereof. 2.The compound according to claim 1, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷ and R¹⁸ independently from each other are hydrogen, halogen,hydroxy, lower alkyl, lower-alkoxy, fluoro-lower-alkyl,fluoro-lower-alkoxy, hydroxy-lower-alkyl, aryl or cyano.
 3. The compoundaccording to claim 1, wherein V is —C(R⁷)— and R⁷ is as defined inclaim
 1. 4. The compound according to claim 1, wherein W is a singlebond.
 5. The compound according to claim 1, wherein X is O, S, SO₂ orN(R¹⁰) and R¹⁰ is as defined in claim
 1. 6. The compound according toclaim 1, wherein Y is —C(R¹¹R¹²)— or —C(R¹¹R¹²)C(R¹³R¹⁴)—, and R¹¹, R¹²,R¹³ and R¹⁴ are as defined in claim
 1. 7. The compound according toclaim 1, wherein R¹, R², R³, R⁴ and R⁵ independently from each other arehydrogen, halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy,fluoro-lower-alkoxy or NH₂—C(O).
 8. The compound according to claim 1,wherein R¹, R², R³, R⁴ and R⁵ independently from each other arehydrogen, halogen or lower-alkoxy.
 9. The compound according to claim 1,wherein R¹ is lower-alkoxy.
 10. The compound according to claim 1,wherein R¹ is methoxy.
 11. The compound according to claim 1, whereinR², R³ and R⁵ are hydrogen.
 12. The compound according to claim 1,wherein R⁴ is halogen.
 13. The compound according to claim 1, wherein R⁴is chloro.
 14. The compound according to claim 1, wherein R⁶ is an arylor heteroaryl group, which aryl or heteroaryl group is optionallysubstituted by 1 to 4 substituents selected from the group consisting ofhalogen, cyano, lower-alkyl, carboxy-lower-alkyl, lower-alkoxy, COOH,1H-tetrazol-5-yl and 5-oxo-4H-[1,2,4]oxadiazol-3-yl.
 15. The compoundaccording to claim 1, wherein R⁶ is a phenyl, pyridinyl, pyrazolyl orthiazolyl group, which group is optionally substituted by 1 to 2substituents selected from the group consisting of halogen, cyano,lower-alkyl, carboxy-lower-alkyl, lower-alkoxy, COOH, 1H-tetrazol-5-yland 5-oxo-4H-[1,2,4]oxadiazol-3-yl.
 16. The compound according to claim1, wherein R⁶ is a phenyl, pyridinyl or thiazolyl group, which group isoptionally substituted by 1 to 2 substituents selected from the groupconsisting of halogen, carboxy-lower-alkyl and COOH.
 17. The compoundaccording to claim 1, wherein R⁶ is 4-carboxy-phenyl,3-fluoro-4-carboxy-phenyl, 3-chloro-4-carboxy-phenyl,2-carboxy-pyridin-5-yl, 4-carboxy-methyl-phenyl,4-carboxy-methyl-thiazol-2-yl or 2-carboxy-methyl-thiazol-4-yl.
 18. Thecompound according to claim 1, wherein R⁷ is hydrogen, halogen,lower-alkyl, lower-alkoxy or fluoro-lower-alkoxy.
 19. The compoundaccording to claim 1, wherein R⁷ is hydrogen or halogen.
 20. Thecompound according to claim 1, wherein R⁷ is hydrogen or fluoro.
 21. Thecompound according to claim 1 wherein R⁸ and R⁹ are hydrogen.
 22. Thecompound according to claim 1, wherein R¹⁰ is hydrogen.
 23. The compoundaccording to claim 1, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸independently from each other are hydrogen or phenyl.
 24. The compoundaccording to claim 1, wherein R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸are hydrogen.
 25. The compound according to claim 1, wherein R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are hydrogen, COOH or C(O)O-lower-alkyl.26. The compound according to claim 1, selected from the groupconsisting of4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methyl-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-3-methyl-benzoicacid,2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(1H-tetrazol-5-yl)-phenyl]-amide,4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid,5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino)-pyridine-2-carboxylicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-benzoicacid,2-Fluoro-4-{[4-(3-trifluoromethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,2-Fluoro-4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino)-2-fluoro-benzoicacid,2-Fluoro-4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,4-[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[4-(3-Carbamoyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,6-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-nicotinicacid,2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid,3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid phenylamide,3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid pyridin-3-ylamide,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[9-(5-Chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[9-(5-chloro-2-methoxy-benzenesulfonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-carbonyl]-amino}-benzoicacid,4-{[6-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[6-(5-chloro-2-methoxy-benzenesulfonyl)-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazocine-8-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methoxy-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[7-Chloro-3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[8-Chloro-4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylicacid (4-fluoro-phenyl)-amide,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carbonyl]-amino}-benzoicacid,1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylicacid phenylamide,4-(5-Chloro-2-methoxy-benzenesulfonyl)-4H-benzo[1,4]oxazine-6-carboxylicacid phenylamide,(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid,(4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid,(2-[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid,(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-fluoro-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylicacid phenylamide,3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-benzoicacid,(2-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-thiazol-4-yl)-aceticacid, and(4-{[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,4-dihydro-2H-benzo[d][1,3]oxazine-7-carbonyl]-amino}-phenyl)-aceticacid, and pharmaceutically acceptable salts and esters thereof.
 27. Thecompound according to claim 1, selected from the group consisting of4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,2-Chloro-4-[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,5-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyridine-2-carboxylicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoxaline-6-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoicacid,4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid, and(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid, and4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid, and pharmaceutically acceptable salts and esters thereof.
 28. Thecompound according to claim 1, selected from the group consisting of2-Chloro-5-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-trifluoromethyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-phenyl)-aceticacid,(2-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-7-methyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-5-yl)-aceticacid,2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-5-carboxylicacid,(3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid,3-(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-propionicacid,(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-5-methyl-thiazol-4-yl)-aceticacid,(3-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-pyrazol-1-yl)-aceticacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-cyano-benzoicacid,2-Fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoicacid,(2-{[4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(2-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(2-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid,(3-{[3-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-pyrazol-1-yl)-aceticacid,4-{[4-(3-Chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Chloro-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3-Chloro-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3,5-Dimethyl-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(3,5-Dimethyl-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1-oxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid,(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-phenyl)-aceticacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-2-fluoro-benzoicacid,2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,2-Chloro-4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-benzo[1,4]thiazine-6-carbonyl]-amino}-benzoicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-phenylcarbamoyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(2-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(3-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid,4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid ethyl ester, and4-(5-Chloro-2-methoxy-benzenesulfonyl)-6-(4-fluoro-phenylcarbamoyl)-3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylicacid and pharmaceutically acceptable salts and esters thereof.
 29. Thecompound according to claim 1, selected from the group consisting of(2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-aceticacid, and(4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-8-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-phenyl)-aceticacid and pharmaceutically acceptable salts and esters thereof.
 30. Aprocess for the manufacture of compounds of formula (I) as defined inclaim 1, comprising the step of: a) reacting a compound of formula (XIV)

with a compound of formula (XV)

or b) reacting a compound of formula (XVI)

with a compound R⁶—NH₂, wherein R¹, R², R³, R⁴, R⁵, R⁶, V, W, X and Yare as defined in any of claims 1-29.
 31. A pharmaceutical composition,comprising a therapeutically effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier and/or adjuvant.
 32. Amethod for the therapeutic and/or prophylactic treatment of diseaseswhich are modulated by L-CPT1 inhibitors, comprising the step ofadministering a therapeutically effective amount of a compound accordingto claim 1 to a human being or animal in need thereof.
 33. The methodaccording to claim 32, wherein said diseases are hyperglycemia, glucosetolerance disorders, diabetes and associated pathologies, non insulindependent diabetes mellitus, obesity, hypertension, insulin resistancesyndrome, metabolic syndrome, hyperlipidemia, hypercholesterolemia,fatty liver disease, atherosclerosis, congestive heart failure or renalfailure,